Elucidating ascorbate and aldarate metabolism pathway characteristics via integration of untargeted metabolomics and transcriptomics of the kidney of high-fat diet-fed obese mice.

Obesity is a major independent risk factor for chronic kidney disease and can activate renal oxidative stress injury. Ascorbate and aldarate metabolism is an important carbohydrate metabolic pathway that protects cells from oxidative damage. However the effect of oxidative stress on this pathway is still unclear. Therefore, the primary objective of this study was to investigate the ascorbate and aldarate metabolism pathway in the kidneys of high-fat diet-fed obese mice and determine the effects of oxidative stress. Male C57BL/6J mice were fed on a high-fat diet for 12 weeks to induce obesity. Subsequently, non-targeted metabolomics profiling was used to identify metabolites in the kidney tissues of the obese mice, followed by RNA sequencing using transcriptomic methods. The integrated analysis of metabolomics and transcriptomics revealed the alterations in the ascorbate and aldarate metabolic pathway in the kidneys of these high-fat diet-fed obese mice. The high-fat diet-induced obesity resulted in notable changes, including thinning of the glomerular basement membrane, alterations in podocyte morphology, and an increase in oxidative stress. Metabolomics analysis revealed 649 metabolites in the positive-ion mode, and 470 metabolites in the negative-ion mode. Additionally, 659 differentially expressed genes (DEGs) were identified in the obese mice, of which 34 were upregulated and 625 downregulated. Integrated metabolomics and transcriptomics analyses revealed two DEGs and 13 differential metabolites in the ascorbate and aldarate metabolic pathway. The expression levels of ugt1a9 and ugt2b1 were downregulated, and the ascorbate level in kidney tissue of obese mice was reduced. Thus, renal oxidative stress injury induced by high-fat diet affects metabolic regulation of ascorbate and aldarate metabolism in obese mice. Ascorbate emerged as a potential marker for predicting kidney damage due to high-fat diet-induced obesity.

Beyond the ß-amino alcohols framework: identification of novel ß-hydroxy pyridinium salt-decorated pterostilbene derivatives as bacterial virulence factor inhibitors.

BACKGROUND: Bacterial virulence factors are involved in various biological processes and mediate persistent bacterial infections. Focusing on virulence factors of phytopathogenic bacteria is an attractive strategy and crucial direction in pesticide discovery to prevent invasive and persistent bacterial infection. Hence, discovery and development of novel agrochemicals with high activity, low-risk, and potent anti-virulence is urgently needed to control plant bacterial diseases. RESULTS: A series of novel ß-hydroxy pyridinium cation decorated pterostilbene derivatives were prepared and their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) were systematacially assessed. Among these pterostilbene derivatives, compound 4S exhibited the best antibacterial activity against Xoo in vitro, with an half maximal effective concentration (EC50) value of 0.28 µg mL-1. A series of biochemical assays including scanning electron microscopy, crystal violet staining, and analysis of biofilm formation, swimming motility, and related virulence factor gene expression levels demonstrated that compound 4S could function as a new anti-virulence factor inhibitor by interfering with the bacterial infection process. Furthermore, the pot experiments provided convinced evidence that compound 4S had the high control efficacy (curative activity: 71.4%, protective activity: 72.6%), and could be used to effectively manage rice bacterial leaf blight in vivo. CONCLUSION: Compounds 4S is an attractive virulence factor inhibitor with potential for application in treating plant bacterial diseases by suppressing production of several virulence factors. © 2024 Society of Chemical Industry.

Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2.

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.

Sulfonamide disinfection byproducts exhibited severe toxicity to human commensal bacteria.

Many antibiotic disinfection byproducts have been detected but their toxicity has not been evaluated adequately. In this report, the chlorination reaction kinetics of five common sulfamides (SAs), reaction intermediates and their toxicity were investigated. Chlorination of sulfapyridine (SPD), sulfamethazine (SMT), sulfathiazole (STZ), and sulfisoxazole (SIZ) followed the second-order kinetics, and were degraded completely within 10 min. A large number of reaction intermediates were deteced by LC-MS, among which a total of 16 intermediates were detected for the first time. Toxicity of the five SAs chlorination solutions was evaluated separately by examining their effects on the growth rate of S. salivarius K12, a commensal bacterium in the human digestive system. After 30 min chlorination, solutions of SMT, STZ and sulfadiazine (SDZ) each exhibited severe toxicity by inhibiting the bacteria growth completely, whereas the inhibition was only 50 % and 20  % by SIZ and SPD respectively. Based on the comparison between toxicity test results and mass spectra, three SA chlorination intermediates, m/z 187.2 (C10H10N4), m/z 287.2 (C9H7N3O4S2) and m/z 215 (C7H10N4O2S/C12H14N4) were proposed to be the primary toxicants in the chlorination products. Our study demonstrated the power of combined approach of chemical analysis and toxicity testing in identifying toxic disinfection byproducts, and highlighted the ne ed for more research on the toxicity evaluation and risk assessment of antibiotic disinfection byproducts.

Total Synthesis of Quebrachamine and Kopsiyunnanine D.

The total syntheses of (±)-quebrachamine and (±)-kopsiyunnanine D are reported. Key transformations include an intermolecular Horner-Wadsworth-Emmons olefination to merge the two fragments convergently and an intramolecular Mitsunobu reaction to introduce the synthetically challenging nine-membered azonane ring efficiently.

Bioremediation of 2,4,6-trichlorophenol by extracellular enzymes of white rot fungi immobilized with sodium alginate/hydroxyapatite/chitosan microspheres.

Hydroxyapatite, a calcium phosphate biomass material known for its excellent biocompatibility, holds promising applications in water, soil, and air treatment. Sodium alginate/hydroxyapatite/chitosan (SA-HA-CS) microspheres were synthesized by cross-linking sodium alginate with calcium chloride. These microspheres were carriers for immobilizing extracellular crude enzymes from white rot fungi through adsorption, facilitating the degradation of 2,4,6-trichlorophenol (2,4,6-TCP) in water and soil. At 50 °C, the immobilized enzyme retained 87.2% of its maximum activity, while the free enzyme activity dropped to 68.86%. Furthermore, the immobilized enzyme maintained 68.09% of its maximum activity at pH 7, surpassing the 51.16% observed for the free enzyme. Under optimal conditions (pH 5, 24 h), the immobilized enzymes demonstrated a remarkable 94.7% removal rate for 160 mg/L 2,4,6-TCP, outperforming the 62.1% achieved by free crude enzymes. The degradation of 2,4,6-TCP by immobilized and free enzymes adhered to quasi-first-order degradation kinetics. Based on LC-MS, the plausible biodegradation mechanism and reaction pathway of 2,4,6-TCP were proposed, with the primary degradation product identified as 1,2,4-trihydroxybenzene. The immobilized enzyme effectively removed 72.9% of 2,4,6-TCP from the soil within 24 h. The degradation efficiency of the immobilized enzyme varied among different soil types, exhibiting a negative correlation with soil organic matter content. These findings offer valuable insights for advancing the application of immobilized extracellular crude enzymes in 2,4,6-TCP remediation.

Associations of prenatal exposure to bisphenols with infant anthropometry: A prospective cohort study.

BACKGROUND: Bisphenols (BPs) have been shown to exhibit developmental toxicities. Epidemiological evidence on prenatal BPs exposure and infant growth primarily confined scopes to specific BPs and birth outcomes, with few studies focusing on infant growth and reporting inconsistent findings. The joint effect of prenatal exposure to BPs mixture on infant growth was rarely studied. OBJECTIVE: This study examined associations of prenatal exposure to individual bisphenol A (BPA) and its analogues (bisphenol F [BPF], bisphenol S [BPS], bisphenol AF [BPAF], and tetrachlorobisphenol A [TCBPA]) and their mixture with infant growth. METHODS: Urinary concentrations of BPs in pregnant women were quantified. Weight, body mass index, skinfold thickness, and circumference measurements of infants were collected at birth, 6 and 12 months of age, rapid growth and overweight were further defined. Multiple linear regression models and Bayesian kernel machine regression models (BKMR) were used to analyze associations of exposure to individual BPs and BPs mixture with infants' anthropometric measurements, and to identify the important components among mixture. The risks for rapid growth and overweight of each BP were determined using modified Poisson regression models. RESULTS: A general profile of higher prenatal BPs exposure (mainly BPA, BPF, and BPS) associated with higher anthropometric measurements and higher risks of overweight during infancy was found. We also observed higher risks of rapid growth in infants following prenatal BPs exposure, with risk ratios ranging from 1.46 to 1.91. The joint effect of BPs mixture and single effect of each BP from the BKMR models were consistent with findings from the linear regression models, further suggesting that associations in girls were generally driven by BPA, BPF, or BPS, while in boys mainly by BPF. CONCLUSION: Prenatal exposure to BPs and their mixture could increase anthropometric measurements of offspring during infancy, with implications of altered growth trajectory in future.

The phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity of Forsythiae Fructus: A updated systematic review.

Forsythiae Fructus (FF), the dried fruit of F. suspensa, is commonly used to treat fever, inflammation, etc in China or other Asian countries. FF is usually used as the core herb in traditional Chinese medicine preparations for the treatment of influenza, such as Shuang-huang-lian oral liquid and Yin-qiao powder, etc. Since the wide application and core role of FF, its research progress was summarized in terms of traditional uses, phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity. Meanwhile, the anti-influenza substances and mechanism of FF were emphasized. Till now, a total of 290 chemical components are identified in F. suspensa, and among them, 248 components were isolated and identified from FF, including 42 phenylethanoid glycosides, 48 lignans, 59 terpenoids, 14 flavonoids, 3 steroids, 24 cyclohexyl ethanol derivatives, 14 alkaloids, 26 organic acids, and 18 other types. FF and their pure compounds have the pharmacological activities of anti-virus, anti-inflammation, anti-oxidant, anti-bacteria, anti-tumor, neuroprotection, hepatoprotection, etc. Inhibition of TLR7, RIG-I, MAVS, NF-κB, MyD88 signaling pathway were the reported anti-influenza mechanisms of FF and phenylethanoid glycosides and lignans are the main active groups. However, the bioavailability of phenylethanoid glycosides and lignans of FF in vivo was low, which needed to be improved. Simultaneously, the un-elucidated compounds and anti-influenza substances of FF strongly needed to be explored. The current quality control of FF was only about forsythoside A and phillyrin, more active components should be taken into consideration. Moreover, there are no reports of toxicity of FF yet, but the toxicity of FF should be not neglected in clinical applications.

Supergravity-Steered Generic Manufacturing of Nanosheets-Embedded Nanocomposite Hydrogel with Highly Oriented, Heterogeneous Architecture.

Designing nanocomposite hydrogels with oriented nanosheets has emerged as a promising toolkit to achieve preferential performances that go beyond their disordered counterparts. Although current fabrication strategies via electric/magnetic force fields have made remarkable achievements, they necessitate special properties of nanosheets and suffer from an inferior orientation degree of nanosheets. Herein, a facile and universal approach is discovered to elaborate MXene-based nanocomposite hydrogels with highly oriented, heterogeneous architecture by virtue of supergravity to replace conventional force fields. The key to such architecture is to leverage bidirectional, force-tunable attributes of supergravity containing coupled orthogonal shear and centrifugal force field for steering high-efficient movement, pre-orientation, and stacking of MXene nanosheets in the bottom. Such a synergetic effect allows for yielding heterogeneous nanocomposite hydrogels with a high-orientation MXene-rich layer (orientation degree, f = 0.83) and a polymer-rich layer. The authors demonstrate that MXene-based nanocomposite hydrogels leverage their high-orientation, heterogeneous architecture to deliver an extraordinary electromagnetic interference shielding effectiveness of 55.2 dB at 12.4 GHz yet using a super-low MXene of 0.3 wt%, surpassing most hydrogels-based electromagnetic shielding materials. This versatile supergravity-steered strategy can be further extended to arbitrary nanosheets including MoS2, GO, and C3N4, offering a paradigm in the development of oriented nanocomposites.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells.

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

Daphmacrimines A-K, Daphniphyllum alkaloids from Daphniphyllum macropodum Miq.

Daphmacrimines A-K (1-11) were isolated from the leaves and stems of Daphniphyllum macropodum Miq. Their structures and stereochemistries were determined by extensive techniques, including HRESIMS, NMR, ECD, IR, and single-crystal X-ray crystallography. Daphmacrimines A-D (1-4) are unprecedented Daphniphyllum alkaloids with a 2-oxazolidinone ring. Daphmacrimine I (9) contains a nitrile group, which is relatively rare in naturally occurring alkaloids. The abilities of daphmacrimines A-D and daphmacrimines G-K to enhance lysosomal biogenesis were evaluated through LysoTracker Red staining. Daphmacrimine K (11) can induce lysosomal biogenesis and promote autophagic flux.

Pain Comorbidities with Attention Deficit: A Narrative Review of Clinical and Preclinical Research.

A negative correlation exists between attention and pain. The cognitive impairments linked to pain can significantly impede a patient's healing process and everyday tasks, particularly for individuals experiencing persistent pain. Furthermore, it has been demonstrated that diversion can effectively decrease pain levels in individuals. The focus of this review is to analyze clinical trials and fundamental investigations regarding alterations in focus and persistent discomfort. Moreover, we investigated the common neuroanatomy associated with attention and pain. Furthermore, we examined the impact of various neuromodulators on the transmission of pain and processes related to attention, while also considering the potential neural mechanisms that contribute to the co-occurrence of pain and attention deficits. Further investigation in this field will enhance our comprehension of patient symptoms and the underlying pathophysiology, ultimately resulting in more objective approaches to treatment.

Year in Review 2023: Noteworthy Literature in Cardiothoracic Transplantation.

This review highlights key studies examining perioperative management of cardiothoracic transplantation published in 2023. Articles were manually screened after searching Scopus, PubMed, and Google Scholar databases for manuscripts related to cardiothoracic transplantation, which yielded 343 papers with 15 qualitatively selected as the most salient for readers. Overarching themes include differences in outcomes across the various etiologies of end-stage lung disease, novel developments to expand the donor pool, and multi-organ transplantation.

Antifungal Activity and Putative Mechanism of HWY-289, a Semisynthetic Protoberberine Derivative, against Botrytis cinerea.

The emergence of resistant pathogens has increased the demand for alternative fungicides. The use of natural products as chemical scaffolds is a potential method for developing fungicides. HWY-289, a semisynthetic protoberberine derivative, demonstrated broad-spectrum and potent activities against phytopathogenic fungi, particularly Botrytis cinerea (with EC50 values of 1.34 µg/mL). SEM and TEM imaging indicated that HWY-289 altered the morphology of the mycelium and the internal structure of cells. Transcriptomics revealed that it could break down cellular walls through amino acid sugar and nucleotide sugar metabolism. In addition, it substantially decreased chitinase activity and chitin synthase gene (BcCHSV) expression by 53.03 and 82.18% at 1.5 µg/mL, respectively. Moreover, this impacted the permeability and integrity of cell membranes. Finally, HWY-289 also hindered energy metabolism, resulting in a significant reduction of ATP content, ATPase activities, and key enzyme activities in the TCA cycle. Therefore, HWY-289 may be a potential candidate for the development of plant fungicides.

Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin-Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment.

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)-indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA-IND-C4 complex (HSA-IND-C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA-IND-C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.

Enhanced bioremediation of organically combined contaminated soil by white rot fungal agent: physiological characteristics and contaminants degradation.

Microbial remediation of organically combined contaminated sites is currently facing technical challenges. White rot fungi possess broad-spectrum degradation capabilities, but most of the studies are conducted on polluted water bodies, and few research focus on the degradation of combined organically contaminated soils. This study aimed to investigate the physiological changes in Trametes versicolor to enhance its simultaneous degradation ability towards benzo(a)pyrene (BaP) and TPH. The results demonstrated that Trametes versicolor, when subjected to liquid fermentation, achieved an 88.08% degradation of individual BaP within 7 days. However, under the combined contamination conditions of BaP and TPH, the BaP degradation rate decreased to 69.25%, while the TPH degradation rate was only 16.95%. Furthermore, the degradation rate of BaP exhibited a significant correlation with the extracellular protein concentration and laccase activities. Conversely, the TPH degradation rate exhibited a significant and positive correlation with the intracellular protein concentration. Solid-state fermentation utilizing fungal agents proved to be the most effective method for removing BaP and TPH, yielding degradation rates of 56.16% and 15.73% respectively within 60 days. Overall, Trametes versicolor demonstrated a commendable capability for degrading combined PAHs-TPH pollutants, thereby providing theoretical insights and technical support for the remediation of organically combined contaminated sites.

Self-Feedback DNAzyme Motor for Cascade-Amplified Imaging of mRNA in Live Cells and In Vivo.

DNA motors have attracted extensive interest in biosensing and bioimaging. However, the amplification capacity of the existing DNA motor systems is limited since the products from the walking process are unable to feedback into the original DNA motor systems. As a result, the sensitivities of such systems are limited in the contexts of biosensing and bioimaging. In this study, we report a novel self-feedback DNAzyme motor for the sensitive imaging of tumor-related mRNA in live cells and in vivo with cascade signal amplification capacity. Gold nanoparticles (AuNPs) are modified with hairpin-locked DNAzyme walker and track strands formed by hybridizing Cy5-labeled DNA trigger-incorporated substrate strands with assistant strands. Hybridization of the target mRNA with the hairpin strands activates DNAzyme and promotes the autonomous walking of DNAzyme on AuNPs through DNAzyme-catalyzed substrate cleavage, resulting in the release of many Cy5-labeled substrate segments containing DNA triggers and the generation of an amplified fluorescence signal. Moreover, each released DNA trigger can also bind with the hairpin strand to activate and operate the original motor system, which induces further signal amplification via a feedback mechanism. This motor exhibits a 102-fold improvement in detection sensitivity over conventional DNAzyme motors and high selectivity for target mRNA. It has been successfully applied to distinguish cancer cells from normal cells and diagnose tumors in vivo based on mRNA imaging. The proposed DNAzyme motor provides a promising paradigm for the amplified detection and sensitive imaging of low-abundance biomolecules in vivo.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

MOCAT: multi-omics integration with auxiliary classifiers enhanced autoencoder.

BACKGROUND: Integrating multi-omics data is emerging as a critical approach in enhancing our understanding of complex diseases. Innovative computational methods capable of managing high-dimensional and heterogeneous datasets are required to unlock the full potential of such rich and diverse data. METHODS: We propose a Multi-Omics integration framework with auxiliary Classifiers-enhanced AuToencoders (MOCAT) to utilize intra- and inter-omics information comprehensively. Additionally, attention mechanisms with confidence learning are incorporated for enhanced feature representation and trustworthy prediction. RESULTS: Extensive experiments were conducted on four benchmark datasets to evaluate the effectiveness of our proposed model, including BRCA, ROSMAP, LGG, and KIPAN. Our model significantly improved most evaluation measurements and consistently surpassed the state-of-the-art methods. Ablation studies showed that the auxiliary classifiers significantly boosted classification accuracy in the ROSMAP and LGG datasets. Moreover, the attention mechanisms and confidence evaluation block contributed to improvements in the predictive accuracy and generalizability of our model. CONCLUSIONS: The proposed framework exhibits superior performance in disease classification and biomarker discovery, establishing itself as a robust and versatile tool for analyzing multi-layer biological data. This study highlights the significance of elaborated designed deep learning methodologies in dissecting complex disease phenotypes and improving the accuracy of disease predictions.

Designing a Mitochondria-Targeted Theranostic Cyclometalated Iridium(III) Complex: Overcoming Cisplatin Resistance and Inhibiting Tumor Metastasis through Necroptosis and Immune Response.

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response.