In recent years, antiaromatic compounds have gained significant attention in optoelectronic materials, catalytic synthesis, and biomedicine due to their unique electronic structures and properties, emerging as a research frontier in organic chemistry. Over the past five years, a variety of novel antiaromatic metallacycles have been reported. Their electronic structures, however, differ significantly from those of conventional antiaromatic systems due to the involvement of transition metal d orbitals. In this context, computational methods, particularly density functional theory, play an important role in evaluating and understanding antiaromaticity. This paper reviews representative examples of antiaromatic metallacycles reported in the past five years, with particular emphasis on the critical role of computational chemistry methods in characterizing their antiaromatic nature, aiming to provide valuable insights for future research in this rapidly evolving area.

Neutrophils exhibit significant heterogeneity and functional plasticity in both healthy and disease states. Patients often suffer from multiple conditions simultaneously, complicating disease-associated neutrophil functions. This complexity challenges tumor-related research, yet current studies frequently overlook the functional differences of neutrophils across health and disease, which may contribute to unsatisfactory anti-tumor drug outcomes. This article reviews six conditions that affect neutrophil functions and influence tumor treatment efficacy: inflammation, aging, obesity, diabetes, thrombosis, and liver injury. It highlights how neutrophil phenotypes and functions change under these conditions, potentially altering their roles in tumor immunity and impacting anti-tumor therapies. Furthermore, four anti-tumor strategies targeting neutrophils are discussed, such as neutrophil drug delivery systems, neutrophil reprogramming, regulation of neutrophil extracellular traps, and the use of neutrophil membranes and exosomes. This review offers a novel perspective: for cancer patients with concurrent comorbidities (such as inflammation, aging, obesity, diabetes, thrombosis, and liver injury), tailoring treatment by targeting or leveraging neutrophils in these disease states may be of significant importance.

A switchable supramolecular solvent based dispersive liquid-liquid microextraction method was developed for the preconcentration and determination of six main hepatotoxic ingredients in Chinese herbal medicine of "Psoraleae Fructus" combined with high performance liquid chromatography-ultraviolet detection. Based on the biodegradable alkyl polyglucoside and a switchable deep eutectic solvent composed of diethanolamine and hexanoic acid, a hydrophilic supramolecular solvent was prepared for the extraction of the target analytes from the aqueous sample solution, and the phase separation was obtained by adding hydrochloric acid solution. A combination of one-factor-at-a-time and central composite design was employed to investigate the primary factors influencing the extraction efficiency, including the composition and volume of alkyl polyglucoside-based switchable supramolecular solvent, the type and dosage of phase-switching trigger, extraction time and salt concentration of the sample solution. Under the optimal extraction conditions, the performance metrics of the proposed method were validated, demonstrating good linearity (r ≥ 0.9979), low detection limits, satisfactory precisions (relative standard deviation≤6.4%) and spiked recoveries (90.3%-107.8%). The enrichment factors for six target analytes ranged from 64 to 666 greater than the published reports. The formation of the supramolecular solvent was characterized by utilizing Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. The extraction mechanism was elucidated by analytes properties, theoretical calculation and the molecular docking. The greenness of the proposed method was assessed by AGREE and AGREEprep tools. The established method possessed good extraction efficiency and could effectively enrich the components with varying polarities in complex matrices.

Immunogenic cell death (ICD) provides a promising strategy for cancer treatment by stimulating anti-tumor immunity. However, single ICD inducers often elicit insufficient damage-associated molecular patterns (DAMPs), and the rapid clearance of these DAMPs at the tumor site further prevents sustained immune stimulation. To address these challenges, we developed a polyphenol-based bioadhesive hydrogel antigen reservoir functionalized with dopamine (DA) and loaded with dual ICD inducers. Specifically, thymidine kinase (tk)-deficient oncolytic vaccinia virus (VV, a type II ICD inducer) was combined with oxaliplatin (OXA, a type I ICD inducer), thereby enhancing direct tumor cytotoxicity and synergistically amplifying ICD through distinct mechanisms to promote robust DAMP release. Subsequently, the released DAMPs were captured and retained by the DA-functionalized hyaluronic acid-Pluronic® F127 hydrogel (HADP), forming an antigen reservoir at the tumor site. This synergistic “stimulate-and-retain” strategy not only augments ICD-mediated DAMP release but also prolongs their local availability to sustain immune stimulation. In murine models, the OXA-HADP@VV facilitated dendritic cell (DC) activation, increased IFN-γ+CD8+ T cell infiltration, and reduced regulatory T cells (Tregs), thereby achieving effective tumor suppression and strong anti-recurrence effects. Together, this dual ICD-inducing antigen reservoir provides a versatile platform for improving cancer immunotherapy.

Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies. Doxorubicin is a powerful cancer drug, but it can harm the heart, leading to a condition called doxorubicin-induced cardiotoxicity (DIC). Some people are more affected by DIC than others, and scientists want to understand why. They found that the heterogeneity observed among endothelial cells (ECs) plays a potential role in determining DIC sensitivity. In mice less sensitive to DIC, reprogramming of ECs increases levels of P-glycoprotein (P-gp), which helps to pump drugs out of cells. They discovered that activating a pathway involving IFN-γ increased P-gp levels, reducing heart damage. Conversely, activating another pathway, PPAR-γ, decreased P-gp levels and increased heart damage. These findings provide new insights into DIC pathogenesis and suggest that boosting P-gp in ECs could be a new strategy to protect against DIC. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Bruton's tyrosine kinase (BTK) is a crucial enzyme in the B cell receptor signaling pathway. It plays a central role in B cell development, maturation, and signaling. This role extends to the survival, proliferation, and migration of malignant B cells, making BTK an intriguing target in the search for therapeutics against B cell malignancies. Our research focused on the discovery of a covalent inhibitor of BTK with good selectivity and potency and a favorable safety profile. We identified compound 22, an imidazo[1,2-b]pyridazine derivative, exhibiting potent BTK inhibition (IC50 1.3 nM) with excellent selectivity across 310 kinases. Compound 22 demonstrated favorable pharmacokinetics and a robust safety profile. In a xenograft model, it significantly inhibited tumor growth, achieving complete tumor regression in 7 out of 10 mice at a dose of 15 mg/kg. This promising preclinical data led to the advancement of compound 22, named TM471-1, into Phase I clinical trials (CXHL2300956).

The synthesis of allylic amines through an outer-sphere nucleophilic substitution mechanism involving electrophilic allyl copper(III) complexes with soft amines represents an uncharted territory in catalysis. This study introduces a radical-based approach for the generation of allylic copper(III) complexes, enabling the efficient synthesis of allylic amines in the presence of alkyl/aryl amines. Through copper photocatalysis, we demonstrate a radical-induced small-ring opening process that produces allylic amines featuring skipped double bonds, while simultaneously achieving highly regioselective 1,4-carboamination of 1,3-dienes with high E/Z selectivity. Mechanism studies substantiate the radical-mediated formation of allylic copper complexes and provide evidence for the involvement of outer-sphere nucleophilic substitution at allylic copper(III) complexes.

Curcumin, a bioactive compound extracted from Curcuma longa. L., demonstrates significant therapeutic potential in inflammatory diseases. This study aims to explore the effects of curcumin on hyperuricemia with acute gout and associated renal dysfunction in a mouse model. The results show that curcumin treatment alleviates ankle joint swelling, reduces inflammatory cytokines IL‐1 β and TNF‐ α , and lowers serum uric acid concentrations. High‐dose curcumin notably inhibits xanthine oxidase (XOD) activity, a key enzyme in uric acid production, while it enhances the renal expression of the urate transporter ABCG2, thereby promoting uric acid excretion. Furthermore, curcumin effectively mitigates renal injury as evidenced by reduced serum creatinineand blood urea nitrogen levels and suppresses renal inflammation. At the molecular level, curcumin exerts potent antioxidant effects by lowering reactive oxygen species (ROS) levels in both cultured HK‐2 human renal tubular epithelial cells and RAW264.7 mouse macrophages. The curcumin‐mediated effects are associated with the disruption of NEK7‐NLRP3 complex formation, leading to the suppression of the ROS/NEK7‐NLRP3 inflammasome pathway. This, in turn, inhibits pyroptosis and the subsequent release of mature IL‐1 β . These findings suggest that curcumin not only reduces uric acid production but also modulates inflammation through ROS‐scavenging properties and its ability to inhibit the NLRP3 inflammasome.

To address the limitations of single therapy and ensure the safe and efficient delivery of nanomedicine, we developed carbon/manganese nanoparticles (NPs). These NPs were engineered by depositing manganese dioxide on the surface of mesoporous carbon (MMCN), thus enabling Peroxidase (POD)-Catalase (CAT)-Glutathione peroxidase (GPX)-like function. Following the modification with AS1411 aptamer (AMMCN), doxorubicin hydrochloride (DOX) was incorporated to produce AMMCN@DOX. This compound demonstrated satisfactory biocompatibility, efficient tumor tissue accumulation, and the capability to release DOX in response to the tumor microenvironment (TME). It was confirmed that AMMCN@DOX is effectively endocytosed by cells, releases DOX, decomposes H2O2 to generate O2 to alleviate tumor hypoxia, and mediates a Fenton-like reaction. Additionally, AMMCN@DOX showed excellent photothermal conversion efficiency, producing localized heating in tumors and yielding superior synergistic anti-tumor activity in mice with solid tumors. Thus, this study proposes a safe, targeted delivery strategy for carbon/manganese NPs, facilitating chemical, chemokinetic, and photothermal synergistic therapy.

The Ru complexes have garnered a great deal of attention for antitumor phototherapy; however, achieving efficient cellular uptake and tumor-specific activation represents a major challenge. Herein, we synthesize a hypoxia-activated Ru complex (RuANM) and construct it into supramolecular polymers (PolyRuANM) through high binding affinity interaction. The amphiphilic supramolecular polymers possess self-assembly, resulting in the formation of diverse nanostructures exhibiting a range of morphologies by simply adjusting the host-guest ratio. As the polymer nanostructure size and morphology have been optimized, PolyRuANM prevents premature drug leakage and accumulates rapidly in the tumor cells. In the tumor hypoxia microenvironment, the polymer undergoes selective activation and disintegration, leading to the unlock of Ru complexes. Notably, the subsequent application of red light irradiation exacerbates the hypoxia and potentiates the liberation of the Ru complexes. This polymer design concept provides some novel insights into on-demand drug delivery and smart chemophotodynamic therapy.

Zanthoxylum plants are usually deciduous trees or shrubs of Rutaceae, as industrial crops widely cultivated in China. Three representative Zanthoxylum species, Z. bungeanum, Z. schinifolium, and Z. armatum, are well-known for their pericarps rich in bioactive compounds and can be utilized as functional additives or phytomedicine. These mentioned Zanthoxylum species are distributed and intermixed with each other as “Zanthoxylum” on markets, which creates obstacles for consumers to identify them. In the present study, 49 batches of Zanthoxylum extracts were examined for anti-inflammatory activity and then employed in acquiring corresponding multi-constituent profiles by UHPLC-Q-Orbitrap-HRMS and UHPLC-MS/MS. The obtained data were further used for the construction of extreme gradient boosting (XGBoost) classification and regression models. A Shapley additive explanations (SHAP) algorithm was subsequently applied to interpret the XGBoost classification/regression model output for desirable information. Isoquercitrin, rutin, and arctigenin were identified as the important chemical markers for discriminating Zanthoxylum origins through the classification algorithm. Furthermore, six constituents, consisting of hydroxy-γ-sanshool, avicularin, bergapten, rutin, scopoletin, and narcissoside, were screened for their major anti-inflammatory activity by modeling using the regression approach. Unraveling the diversities and connections of constituents and biological activities in these three species could contribute to their reasonable industrial and medicinal applications.

ETHNOPHARMACOLOGICAL RELEVANCE:Atherosclerosis (AS) is one of the main cardiovascular diseases (CVDs) leading to an increase in global mortality, and its key pathological features are lipid accumulation and oxidative stress. Huang-Lian-Jie-Du decoction (HLJDD), a representative formula for clearing heat and detoxifying, has been shown to reduce aortic lipid plaque and improve AS. However, multiple components and multiple targets of HLJDD pose a challenge in comprehending its comprehensive mechanism in the treatment of AS.AIM OF THE STUDY:This study was designed to illustrate the anti-AS mechanisms of HLJDD in an apolipoprotein E-deficient (ApoE-/-) mouse model from a metabolic perspective.MATERIALS AND METHODS:ApoE-/- mice were kept on a high-fat diet (HFD) to induce AS. Serum total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were determined to evaluate the influence of HLJDD on dyslipidemia. Oil red O was used to stain mouse aortic lipid plaques, and hematoxylin and eosin (HE) staining was used to assess the pathological changes in the aortic roots. Metabolomics and lipidomics combined with serum pharmacochemistry were performed to research the HLJDD mechanism of alleviating AS.RESULTS:In this study, HLJDD treatment improved serum biochemical levels and histopathological conditions in AS mice. A total of 6 metabolic pathways (arginine biosynthesis, glycerophospholipid, sphingolipid, arachidonic acid, linoleic acid, and glycerolipid metabolism) related to 25 metabolic biomarkers and 41 lipid biomarkers were clarified, and 22 prototype components migrating to blood were identified after oral administration of HLJDD.CONCLUSION:HLJDD improved AS induced by HFD in ApoE-/- mice. The effects of HLJDD were mainly attributed to regulating lipid metabolism by regulating the metabolic pathways of glycerophospholipids, sphingolipids, arachidonic acid, linoleic acid, and glycerolipids and reducing the levels of oxidative stress by upregulating arginine biosynthesis.

The unsatisfactory efficacy of immunotherapy for colorectal cancer (CRC) remains a major challenge for clinicians and patients. The tumor microenvironment may promote CRC progression by upregulating the expression of hypoxia-inducing factor (HIF) and PD-L1. Therefore, this study explored the expression and correlation of HIF-1α and PD-L1 in the CRC microenvironment. The expression and correlation of HIF-1α and PD-L1 in CRC were analyzed using bioinformatics and Western blotting (WB). The hypoxia and inflammation of the CRC microenvironment were established in the CT26 cell line. CT26 cells were stimulated with two hypoxia mimics, CoCl2 and DFO, which were used to induce the hypoxic environment. Western blotting was used to assess the expression and correlation of HIF-1α and PD-L1 in the hypoxic environment.LPS stimulated CT26 cells to induce the inflammatory environment. WB and bioinformatics were used to assess the expression and correlation of TLR4, HIF-1α, and PD-L1 in the inflammatory environment. Furthermore, the impact of curcumin on the inflammatory environment established by LPS-stimulated CT26 cells was demonstrated through MTT, Transwell, molecular docking, network pharmacology and Western blotting assays. In this study, we found that the HIF-1α/PD-L1 pathway was activated in the hypoxic and inflammatory environment and promoted immune escape in CRC. Meanwhile, curcumin suppressed tumor immune escape by inhibiting the TLR4/HIF-1α/PD-L1 pathway in the inflammatory environment of CRC. These results suggest that combination therapy based on the HIF-1α/PD-L1 pathway can be a promising therapeutic option and that curcumin can be used as a potent immunomodulatory agent in clinical practice.

A new radical difluoromethylation was developed by using inexpensive and readily available difluoroacetic anhydride and N-phenyl-4-methylbenzenesulfonamide for the first time. The reaction of arylboronic acids with the new difluoromethylation reagent, N-phenyl-N-tosyldifluoroacetamide, proceeded smoothly in the presence of palladium catalyst to provide difluoromethylarenes in satisfactory to excellent yields. The electronic property (electron-donating or electron-withdrawing) of the substituent linked to the aromatic ring did not considerably influence the reactivity of arylboronic acid. Various groups, including the synthetically useful functional groups Cl, CN, and NO2, were tolerated well under the current reaction conditions.

A new trifluoroacetylation reagent was developed by using inexpensive and readily available trifluoroacetic anhydride and N-phenyl-4-methylbenzenesulfonamide for the first time. The reaction of (het)aryl boronic acids with the new trifluoroacetylation reagent, N-phenyl-N-tosyltrifluoroacetamide, proceeded smoothly in the presence of a palladium catalyst to provide trifluoromethyl ketones in satisfactory to excellent yields. Various groups, including the synthetically useful functional groups Cl, TMS, and PhCO, were tolerated well under the current reaction conditions. This new trifluoroacetylation reagent can be used in the large-scale synthesis of trifluoromethyl ketones, even at a low palladium catalyst loading.

A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 +/- 0.25 mu Mu) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE(2) in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA(2), and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA(2) and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA(2)/COX-2/PGE(2) pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA(2) and COX-2 play a role in their etiology.

Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds were initially screened for in vitro anti-inflammatory activity by assessing their inhibitory effect on NO release in LPS-stimulated RAW264.7 cells, and the optimal compound was finally identified as 2-(3-Methoxyphenyl)- N '-((6 Z ,9 Z ,12 Z ,15 Z )-1,1,1-trifluorohenicosa-6,9,12,15- tetraen-2-ylidene)acetohydrazide ( F26 , IC 50 = 4.55 +/- 0.92 uM) with no cytotoxicity. Moreover, F26 potently reduced the production of PGE 2 in LPS-stimulated RAW264.7 cells compared to indomethacin. The interaction of F26 with COX -2 and cPLA 2 was directly verified by the CETSA technique. F26 was found to modulate the phosphorylation levels of p38 MAPK and NF-xB p65, as well as the protein expression of IxB, cPLA 2 , COX -2, and iNOS in LPS-stimulated rat peritoneal macrophages. Additionally, F26 was observed to prevent the nuclear translocation of NF-xB p65 in LPS-stimulated rat peritoneal macrophages by immunofluorescence localization. Therefore, the aforementioned in vitro experiments demonstrated that F26 blocked the p38 MAPK and NF-xB pathways by binding to COX -2 and cPLA 2 . In the adjuvant -induced arthritis model, F26 demonstrated a significant effect in preventing arthritis symptoms and inflammatory status in rats, exerting an immunomodulatory role by regulating the homeostasis between Th17 and Treg through inhibition of the p38 MAPK/cPLA 2 /COX-2/ PGE 2 and NF-xB pathways. Encouragingly, F26 caused less acute ulcerogenicity in rats at a dose of 50 mg/kg compared to indomethacin. Overall, F26 is a promising candidate worthy of further investigation for treating inflammation and associated pain with lesser gastrointestinal irritation, as well as other symptoms in which cPLA 2 and COX -2 are implicated in the pathophysiology.

Chlorogenic acid and caffeic acid are the main active components that exhibit a clearing heat-toxin effect in Chinese medicinal formulae (CMF). However, they have very low content and coexist with many structural analogues and a large number of interfering substances in complex CMF samples, making it difficult to effectively separate and analyze them. Herein, we synthesized epitope-imprinted magnetic nanoparticles (EIMNPs) using a reverse microemulsion-based interface imprinting strategy for specific extraction of chlorogenic acid and caffeic acid from CMF. A dual surfactant reverse microemulsion system was constructed by cetyltrimethylammonium bromide (CTAB) and Triton X-100. Caffeic acid as an epitope template for chlorogenic acid was confined to the oil/water interface through electrostatic attraction between its carboxyl anion and the quaternary ammonium salt cation of CTAB. Hydrophilic polyethylene glycol-coated Fe3O4 magnetic nanoparticles served as substrates. Aminopropyltriethoxysilane, 3-ureidopropyltriethoxysilane, and benzyltriethoxysilane as functional monomers and tetraethyl orthosilicate as a crosslinker were selected. The prepared EIMNPs exhibited excellent specificity for chlorogenic acid and caffeic acid, and their imprinting factors were 4.5 and 6.6, respectively. In addition, the EIMNPs had rapid magnetic separation property and a fast equilibrium time. The EIMNPs-based affinity extraction coupled with high performance liquid chromatography had been successfully applied to the determination of chlorogenic acid and caffeic acid in a Dachaihu decoction, and their limit of detections were 0.6 ng/ mL and 0.3 ng/mL, respectively. Compared with other imprinting materials, the EIMNPs had significant advantages in imprinting performance and detection sensitivity, and will play an important role in the study of active components in CMF.

Endothelial intercellular pores of tumor vessels generally lead to enhanced interstitial flow and may facilitate the migration of tumor cells. The permeability of tumor vessels causes a concentration gradient of growth factors (CGGF) from blood vessels to tumor tissues, which is opposite to the direction of interstitial flow. In this work, exogenous chemotaxis under the CGGF is demonstrated as a mechanism of hematogenous metastasis. A bionic microfluidic device inspired by endothelial intercellular pores of tumor vessels has been designed to study the mechanism. A porous membrane vertically integrated into the device using a novel compound mold is utilized to mimic the leaky vascular wall. The formation mechanism of the CGGF caused by endothelial intercellular pores is numerically analyzed and experimentally verified. The migration behavior of U-2OS cells is studied in the microfluidic device. The device is divided into three regions of interest (ROI): primary site, migration zone, and tumor vessel. The number of cells in the migration zone increases significantly under the CGGF, but decreases under no CGGF, indicating tumor cells may be guided to the vascellum by exogenous chemotaxis. Transendothelial migration is subsequently monitored, demonstrating the successful replication of the key steps in vitro in the metastatic cascade by the bionic microfluidic device.