Catalyst-Free Synthesis of Thiosulfonates and 3-Sulfenylindoles from Sodium Sulfinates in Water.

This paper presents a green and efficient aqueous-phase method for the synthesis of thiosulfonates, which has the benefits of no need for catalysts or redox reagents and a short reaction time, providing a method with great economic value for synthesizing thiosulfonates. Furthermore, 3-Sulfenylindoles can be easily synthesized using this method, which expands the potential applications of this reaction.

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.

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.

Human Serum Albumin-Platinum(II) Agent Nanoparticles Inhibit Tumor Growth Through Multimodal Action Against the Tumor Microenvironment.

To overcome the limitations of traditional platinum (Pt)-based drugs and further improve the targeting ability and therapeutic efficacy in vivo, we proposed to design a human serum albumin (HSA)-Pt agent complex nanoparticle (NP) for cancer treatment by multimodal action against the tumor microenvironment. We not only synthesized a series of Pt(II) di-2-pyridone thiosemicarbazone compounds and obtained a Pt(II) agent [Pt(Dp44mT)Cl] with significant anticancer activity but also successfully constructed a novel HSA-Pt(Dp44mT) complex nanoparticle delivery system. The structure of the HSA-Pt(Dp44mT) complex revealed that Pt(Dp44mT)Cl binds to the IIA subdomain of HSA and coordinates with His-242. The HSA-His242-Pt-Dp44mT NPs had an obvious effect on the inhibition of tumor growth, which was superior to that of Dp44mT and Pt(Dp44mT)Cl, and they had almost no toxicity. In addition, the HSA-His242-Pt-Dp44mT NPs were found to kill cancer cells by inducing apoptosis, autophagy, and inhibiting angiogenesis.

Novel mono-, bi-, tri- and tetra-nuclear copper complexes that inhibit tumor growth through apoptosis and anti-angiogenesis.

To develop the next-generation metal agents for efficiently inhibiting tumor growth, a series of novel mononuclear, binuclear and trinuclear copper (Cu) thiophene-2-formaldehyde thiosemicarbazone complexes and a tetranuclear Cu 1,2,4-triazole-derived complex have been synthesized and their structure-activity relationships have been studied. The trinucleated Cu complex showed the strongest inhibitory activity against T24 cells among all the Cu complexes. Its antitumor effect in vivo was superior to that of cisplatin, with reduced side effects. Further studies on the antitumor mechanism have showed that Cu complexes not only induced apoptosis of cancer cells but also inhibited tumor angiogenesis by inhibiting the migration and invasion of vascular endothelial cells, blocking the cell cycle in the G1 phase, and inducing autophagy.

Advancements and Perspectives toward Lignin Valorization via O-Demethylation.

Lignin represents the largest aromatic carbon resource in plants, holding significant promise as a renewable feedstock for bioaromatics and other cyclic hydrocarbons in the context of the circular bioeconomy. However, the methoxy groups of aryl methyl ethers, abundantly found in technical lignins and lignin-derived chemicals, limit their pertinent chemical reactivity and broader applicability. Unlocking the phenolic hydroxyl functionality through O-demethylation (ODM) has emerged as a valuable approach to mitigate this need and enables further applications. In this review, we provide a comprehensive summary of the progress in the valorization of technical lignin and lignin-derived chemicals via ODM, both catalytic and non-catalytic reactions. Furthermore, a detailed analysis of the properties and potential applications of the O-demethylated products is presented, accompanied by a systematic overview of available ODM reactions. This review primarily focuses on enhancing the phenolic hydroxyl content in lignin-derived species through ODM, showcasing its potential in the catalytic funneling of lignin and value-added applications. A comprehensive synopsis and future outlook are included in the concluding section of this review.

Developing a Hetero-Trinuclear Erbium(III)-Copper(II) Complex Based on Apoferritin: Targeted Photoacoustic Imaging and Multimodality Therapy of Tumor.

For the integration of targeted diagnosis and treatment of tumor, we innovatively designed and synthesized a single-molecule hetero-multinuclear Er(III)-Cu(II) complex (ErCu2) and then constructed an ErCu2@apoferritin (AFt) nanoparticle (NP) delivery system. ErCu2 and ErCu2@AFt NPs not only provided an evident photoacoustic imaging (PAI) signal of the tumor but also effectively inhibited tumor growth by integrating photothermal therapy, chemotherapy, and immunotherapy. ErCu2@AFt NPs improved the targeting ability and decreased the systemic toxicity of ErCu2 in vivo. Furthermore, we confirmed that ErCu2 and ErCu2@AFt NPs inhibited tumor growth by inducing apoptosis and autophagy of tumor cells and activating the immune system. The study not only provides a novel strategy to develop therapeutic metal agents but also reveals their potential for targeted accurate diagnosis and multimodality therapy of cancer.

Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis.

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth and metastasis, we not only optimized a series of ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain a Ru(III) complex (4b) with remarkable cytotoxicity in vitro but also constructed a 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The in vivo results showed that 4b-DCT-Lip not only had a stronger capacity to inhibit gastric tumor growth and metastasis than 4b-DCT but also addressed the co-delivery problems of 4b-DCT and improved their targeting ability. Furthermore, we confirmed the mechanism of 4b-DCT/4b-DCT-Lip inhibiting the growth and metastasis of a gastric tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 to afford GSDME-N terminal and then was aggregated to form nonselective pores on the cell membrane of a gastric tumor, thereby inducing pyroptosis and a pyroptosis-induced immune response.

Combining hyperspectral imaging techniques with deep learning to aid in early pathological diagnosis of melanoma.

BACKGROUND: Cutaneous melanoma, an exceedingly aggressive form of skin cancer, holds the top rank in both malignancy and mortality among skin cancers. In early stages, distinguishing malignant melanomas from benign pigmented nevi pathologically becomes a significant challenge due to their indistinguishable traits. Traditional skin histological examination techniques, largely reliant on light microscopic imagery, offer constrained information and yield low-contrast results, underscoring the necessity for swift and effective early diagnostic methodologies. As a non-contact, non-ionizing, and label-free imaging tool, hyperspectral imaging offers potential in assisting pathologists with identification procedures sans contrast agents. METHODS: This investigation leverages hyperspectral cameras to ascertain the optical properties and to capture the spectral features of malignant melanoma and pigmented nevus tissues, intending to facilitate early pathological diagnostic applications. We further enhance the diagnostic process by integrating transfer learning with deep convolutional networks to classify melanomas and pigmented nevi in hyperspectral pathology images. The study encompasses pathological sections from 50 melanoma and 50 pigmented nevus patients. To accurately represent the spectral variances between different tissues, we employed reflectance calibration, highlighting that the most distinctive spectral differences emerged within the 500-675 nm band range. RESULTS: The classification accuracy of pigmented tumors and pigmented nevi was 89% for one-dimensional sample data and 98% for two-dimensional sample data. CONCLUSIONS: Our findings have the potential to expedite pathological diagnoses, enhance diagnostic precision, and offer novel research perspectives in differentiating melanoma and nevus.

miR-22 promotes immunosuppression via activating JAK/STAT3 signaling in cutaneous squamous cell carcinoma.

Immunotherapy is the only approved systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC), however, roughly 50% of patients do not respond to the therapy and resistance often occurs over time to those who initially respond. Immunosuppression could have a critical role in developing treatment resistance, thus, understanding the mechanisms of how immunosuppression is developed and regulated may be the key to improving clinical diagnosis and treatment strategies for cSCC. Here, through using a series of immunocompetent genetically engineered mouse models, we demonstrate that miR-22 promotes cSCC development by establishing regulatory T cells (Tregs)-mediated immunosuppressive tumor microenvironment (TME) in a tumor cell autonomous manner. Mechanism investigation revealed that miR-22 elicits the constitutive activation of JAK/STAT3 signaling by directly targeting its suppressor SOCS3, which augments cancer cell-derived chemokine secretion and Tregs recruitment. Epithelial-specific and global knockouts of miR-22 repress papilloma and cSCC development and progression, manifested with reduced Tregs infiltration and elevated CD8+ T cell activation. Transcriptomic analysis and functional rescue study confirmed CCL17, CCL20 and CCL22 as the main affected chemokines that mediate the chemotaxis between miR-22 highly expressing keratinocyte tumor cells and Tregs. Conversely, overexpression of SOCS3 reversed miR-22-induced Tregs recruitment toward tumor cells. Clinically, gradually increasing Tregs infiltration during cSCC progression was negatively correlated with SOCS3 abundance, supported by previously documented elevated miR-22 levels. Thus, our study uncovers a novel miR-22-SOCS3-JAK/STAT3-chemokines regulatory mechanism in defining the immunosuppressive TME and highlights the promising clinical application value of miR-22 as a common targeting molecule against JAK/STAT3 signaling and immune escape in cSCC.

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin.

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

Developing a Gadolinium(III) Compound Based on Apoferritin for Targeted Magnetic Resonance Imaging and Dual-Modal Therapy of Cancer.

To integrate targeted diagnosis and treatment of cancer, we proposed to develop a gadolinium (Gd) agent based on the properties of apoferritin (AFt). To this end, we not only optimized a series of Gd(III) 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazone compounds to obtain a Gd(III) compound (C4) with remarkable T1-weighted magnetic resonance imaging (MRI) performance and cytotoxicity to cancer cells in vitro but also constructed an AFt-C4 nanoparticle (NP) delivery system. Importantly, AFt-C4 NPs improved the targeting ability of C4 in vivo and showed enhanced MRI performance and tumor growth inhibition ratio relative to C4 alone. Furthermore, we confirmed that C4 and AFt-C4 NPs inhibited tumor growth through apoptosis, ferroptosis, and ferroptosis-induced immune response.

Developing an Anticancer Platinum(II) Compound Based on the Uniqueness of Human Serum Albumin.

To develop the next-generation Pt drug with remarkable activity and low toxicity to maximally inhibit tumor growth, we optimized a Pt(II) thiosemicarbazone compound (C4) with remarkable cytotoxicity to SK-N-MC cells and then constructed a new human serum albumin-C4 (HSA-C4) complex delivery system. The in vivo results showed that C4 and the HSA-C4 complex have remarkable therapeutic efficiency and almost no toxicity; they induced apoptosis and inhibited tumor angiogenesis. This system showed potential as a practical Pt drug. This study could pave the way for developing next-generation dual-targeted Pt drugs and achieving their targeting therapy for cancer.

Positive Feedback Regulation of Circular RNA Hsa_circ_0000566 and HIF-1α promotes Osteosarcoma Progression and Glycolysis Metabolism.

Hypoxia is an indispensable factor for cancer progression and is closely associated with the Warburg effect. Circular RNAs (CircRNA) have garnered considerable attention in molecular malignancy therapy as they are potentially important modulators. However, the roles of circRNAs and hypoxia in osteosarcoma (OS) progression have not yet been elucidated. This study reveals the hypoxia-sensitive circRNA, Hsa_circ_0000566, that plays a crucial role in OS progression and energy metabolism under hypoxic stress. Hsa_circ_0000566 is regulated by hypoxia-inducible factor-1α (HIF-1α) and directly binds to it as well as to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase protein. Consequentially, binding between VHL and HIF-1α is impeded. Furthermore, Hsa_circ_0000566 contributes to OS progression by binding to HIF-1α (while competing with VHL) and by confers protection against HIF-1α against VHL-mediated ubiquitin degradation. These findings demonstrate the existence of a positive feedback loop formed by HIF-1α and Hsa_circ_0000566 and the key role they play in OS glycolysis. Taken together, these data indicate the significance of Hsa_circ_0000566 in the Warburg effect and suggest that Hsa_circ_0000566 could be a potential therapeutic target to combat OS progression.

Degradation, isomerization and stabilization of three dicaffeoylquinic acids under ultrasonic treatment at different pH.

Dicaffeoylquinic acids (diCQAs) are found in a variety of edible and medicinal plants with various biological activities. An important issue is the low stability of diCQAs during extraction and food processing, resulting in the degradation and transformation. This work used 3,5-diCQA as a representative to study the influence of different parameters in ultrasonic treatment on the stability of diCQAs, including solvent, temperature, treatment time, ultrasonic power, duty cycle, and probe immersion depth. The generation of free radicals and its influence were investigated during the treatment. The stability of three diCQAs (3,5-diCQA, 4,5-diCQA and 3,4-diCQA) under the certain ultrasonic condition at different pH conditions was evaluated and found to decrease with the increase of pH, further weakened by ultrasonic treatment. Ultrasound was found to accelerate the degradation and isomerization of diCQAs. Different diCQAs showed different pattern of degradation and isomerization. The stability of diCQAs could be improved by adding epigallocatechin gallate and vitamin C.

Chemoenzymatic Cascade Reaction for the Valorization of the Lignin Depolymerization Product G-C2-Dioxolane Phenol.

Combining solid acid catalysts with enzyme reactions in aqueous environments is challenging because either very acidic conditions inactivate the enzymes, or the solid acid catalyst is neutralized. In this study, Amberlyst-15 encapsulated in polydimethylsiloxane (Amb-15@PDMS) is used to deprotect the lignin depolymerization product G-C2 dioxolane phenol in a buffered system at pH 6.0. This reaction is directly coupled with the biocatalytic reduction of the released homovanillin to homovanillyl alcohol by recombinant horse liver alcohol dehydrogenase, which is subsequently acylated by the promiscuous acyltransferase/hydrolase PestE_I208A_L209F_N288A in a one-pot system. The deprotection catalyzed with Amb-15@PDMS attains up to 97 % conversion. Overall, this cascade enables conversions of up to 57 %.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Effect of electric field on coalescence of an oil-in-water emulsion stabilized by surfactant: a molecular dynamics study.

The microscopic understanding of electrocoalescence of oil-in-water (O/W) emulsions stabilized by surfactant is very important to improve the efficiency of electrical demulsification. The behaviors of the coalescence of O/W emulsion stabilized by surfactant in the presence of a direct electric field and a pulsed electric field were explored by nonequilibrium molecular dynamics simulations. According to the simulated results, an electrical method is feasible to demulsify an O/W emulsion stabilized by a surfactant. The configuration and movement of the sodium dodecyl sulfate (SDS) were determined by interactions between SDS molecules themselves and between SDS and oil/water molecules along with the force exerted by the applied electrical field. Two droplets will coalesce into one when the strength of the electric field exceeds 0.4 V nm-1. The SDS group can be broken up by an electric field larger than 0.6 V nm-1. The point when interaction energy between the hexadecane molecules of the two droplets begins to decrease from zero is consistent with the time when the two oil droplets came in contact. The coalescence process can be completed if the two droplets have begun to coalesce, even after the electric field was removed. Otherwise, the coalescence process cannot be completed. To enhance the efficiency of the electrocoalescence of O/W emulsions, strength, frequency and duty ratio of the electric field have to be optimized according to the properties of the emulsion. This research will help us to figure out how electric fields promote the efficiency of electrocoalescence of O/W emulsions with surfactant.