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The diagnosis and treatment of non-small cell lung cancer in clinical settings face serious challenges, particularly due to the lack of integration between the two processes, which limit real-time adjustments in treatment plans based on the patient’s condition and drive-up treatment costs. Here, we present a multifunctional pH-sensitive core-shell nanoparticle containing quercetin (QCT), termed AHA@MnP/QCT NPs, designed for the simultaneous diagnosis and treatment of non-small cell lung cancer. Mechanistic studies indicated that QCT and Mn 2+ exhibited excellent peroxidase-like (POD-like) activity, catalysing the conversion of endogenous hydrogen peroxide into highly toxic hydroxyl radicals through a Fenton-like reaction, depleting glutathione (GSH), promoting reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum, and inducing ferroptosis. Additionally, Mn 2+ could activate the cGAS-STING signalling pathway and promote the maturation of dendritic cells and infiltration of activated T cells, thus inducing tumor immunogenic cell death (ICD). Furthermore, it exhibited effective T2-weighted MRI enhancement for tumor imaging, making them valuable for clinical diagnosis. In vitro and in vivo experiments demonstrated that AHA@MnP/QCT NPs enabled non-invasive imaging and tumor treatment, which presented a one-stone-for-two-birds strategy for combining tumor diagnosis and treatment, with broad potential for clinical application in non-small cell lung cancer therapy. Graphical Abstract

The immunosuppressive tumor microenvironment (TME) is a pivotal contributor to therapeutic resistance in triple-negative breast cancer (TNBC). Immunogenic cell death (ICD), which activates antitumor immunity through damage-associated molecular pattern (DAMP) release, represents a promising therapeutic strategy for TNBC. Although gambogic acid (GA) triggers ICD by inducing synergistic apoptosis/ferroptosis and DAMP secretion, its clinical translation is hindered by non-specific targeting, poor solubility, and systemic toxicity. To overcome these limitations, we engineered homologous tumor cell membrane-coated GA/Ga³⁺ nanoparticles (M@GAGa NPs) that operate through a triple-functionality: (1) Tumor-targeted delivery: Homologous membrane coating enables immune evasion and precise TNBC tissue accumulation. (2) TME-responsive synergy: Acidic TME-triggered release of GA and Ga³⁺ permits Ga³⁺-mediated disruption of tumor metabolism via ferric ion mimicry, synergistically enhancing GA-induced cytotoxicity. (3) Immunomodulation: GA-induced ICD releases immune signalling molecules such as calreticulin (CRT) and high mobility group protein B1 (HMGB1), while Ga³⁺ reprograms immunosuppressive cells, collectively activating dendritic cell (DC) antigen presentation and CD8⁺ T cell-mediated antitumor immunity. M@GAGa NPs remodel the immunosuppressive TNBC microenvironment through multimodal synergy, offering an innovative precision immunotherapy platform to overcome current therapeutic constraints.

The insufficient infiltration and functional inhibition of CD8+ T cells due to tumor microenvironment (TME) are considered enormous obstacles to anti‐tumor immunotherapy. Herein, a pH‐responsive core‐shell manganese phosphate nanomodulator co‐loading siPD‐L1 and Mn2+ into nanoparticles coated with hyaluronic acid was prepared, which was aimed at the bidirectional reprogramming the tumor microenvironment: (1) “Brakes off,” restoring CD8+ T cells function by siPD‐L1 knockdowning PD‐L1 expression of tumor cells; (2) “Step on the accelerator,” promoting CD8+ T cells infiltration in tumors tissue based on the multidimensional immune effects of Mn2+ (immunogenic cell death induced the enhancing cGAS‐STING pathway, the proliferation and maturation of relative immune cells). Additionally, this strategy could induce macrophage polarization and inhibit the regulatory T cells in tumor site. This work provided a manganese phosphate nanomodulator to reprogram the immune TME for an enhanced comprehensive anti‐tumor effect of triple negative breast cancer, which offers a robust method for tumor immunotherapy in future clinical applications. To enhance the comprehensive treatment effect of triple‐negative breast cancer, a pH‐responsive core‐shell manganese phosphate nano‐regulator was prepared to reprogram the tumor microenvironment bi‐directionally. (1) “Brakes off”: Using siPD‐L1 to inhibit PD‐L1 expression to restore CD8+ T cell function. 2) “Step on the accelerator”: Based on Mn2+’s effect, promoting CD8+ T cell infiltration and maturation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a clinicopathological syndrome characterized by abnormal accumulation of fat within hepatocytes, and there is currently no standardized clinical treatment available. Consequently, there is an urgent need to discover new pharmacological interventions and to investigate novel therapeutic targets for MASLD. Melatonin, known for its multifaceted biological functions, has shown therapeutic potential for the treatment of MASLD. However, the underlying mechanisms remain unclear, particularly since the direct targets of melatonin remain poorly understood. In our study, we found that melatonin significantly improved various indicators in a mouse MASLD model and protected palmitic acid-induced mouse hepatocytes from lipid accumulation. We successfully identified and validated the mitochondrial trifunctional enzyme α-subunit HADHA as a binding target for melatonin using the cellular thermal shift assay (CETSA). This interaction enhanced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which subsequently promotes mitochondrial biogenesis and accelerates lipid metabolism. In addition, melatonin reduced lipid accumulation and ameliorated MASLD through its regulatory effect on key proteins involved in fatty acid metabolism, including acyl coenzyme A oxidase 1 (ACOX1), cluster of differentiation 36 (CD36), and fatty acid synthase (FASN). Importantly, these beneficial effects were diminished when HADHA was knocked down. In conclusion, our study suggests that melatonin ameliorates MASLD through HADHA-mediated regulation of mitochondrial biogenesis and lipid oxidation, highlighting its potential as a promising therapeutic agent for MASLD. These results offer novel insights into the role of melatonin in the treatment of MASLD.

The immunosuppressive tumor microenvironment (TME) is a pivotal contributor to therapeutic resistance in triple-negative breast cancer (TNBC). Immunogenic cell death (ICD), which activates antitumor immunity through damage-associated molecular pattern (DAMP) release, represents a promising therapeutic strategy for TNBC. Although gambogic acid (GA) triggers ICD by inducing synergistic apoptosis/ferroptosis and DAMP secretion, its clinical translation is hindered by non-specific targeting, poor solubility, and systemic toxicity. To overcome these limitations, we engineered homologous tumor cell membrane-coated GA/Ga³âº nanoparticles (M@GAGa NPs) that operate through a triple-functionality: (1) Tumor-targeted delivery: Homologous membrane coating enables immune evasion and precise TNBC tissue accumulation. (2) TME-responsive synergy: Acidic TME-triggered release of GA and Ga³âº permits Ga³âº-mediated disruption of tumor metabolism via ferric ion mimicry, synergistically enhancing GA-induced cytotoxicity. (3) Immunomodulation: GA-induced ICD releases immune signalling molecules such as calreticulin (CRT) and high mobility group protein B1 (HMGB1), while Ga³âº reprograms immunosuppressive cells, collectively activating dendritic cell (DC) antigen presentation and CD8⺠T cell-mediated antitumor immunity. M@GAGa NPs remodel the immunosuppressive TNBC microenvironment through multimodal synergy, offering an innovative precision immunotherapy platform to overcome current therapeutic constraints.

Huoxuezhitong rubber patch, a well-known traditional Chinese medicine (TCM) prescription, is utilized to treat pain and inflammation. In this study, a microdialysis-ultra-high-performance liquid chromatography-tandem mass spectrometry (MD-LC-MS/MS) method was designed for the simultaneous determination of active constituents in the rubber patch, such as paeonol (Pae), eugenol (Eug), and piperine (Pip). A microdialysis probe was implanted in the subcutaneous tissue of a rat, which is intended to detect the subcutaneous concentrations of target components. Saline containing 30% ethanol acted as perfusion fluid. Analytes in the microdialysate were completely separated over an ACQITY UPLC RBEH C18 column (2.1mm×100mm, 1.7μm). The mobile phase was composed of 0.01% ammonia aqueous and acetonitrile-0.01% ammonia with gradient elution. The single-run analysis time was 10.0 minutes. The linear regression displayed good linear relationships in the ranges of 0.25–100 ng/mL for paeonol and eugenol and 0.001–5 ng/mL for piperine. The interday and intraday precision of the quality control samples exhibited relative standard deviations (RSD) <13.56%. The accuracy values ranged from −14.92% to 14.00%. The present method was successfully applied in pharmacokinetics studies following dermal administration of Huoxuezhitong rubber patch in rats. Pip’s Tmax (488.00±150.73) min was greater than that of Pae (186.67±48.44) min and Eug (240.00±138.56) min, and the rank order of t1/2 was Pae > Pip > Eug. The rank order of AUC0-720 and Cmax was both Eug > Pae > Pip. MRT0-∞ of Pip was higher than that of Pae and Eug. Eugenol showed a faster elimination and a shorter half-life. Paeonol showed a stronger drug reservoir function after removing the drug source.

Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the cause, classification, and clinicopathological features of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms. 37 cases diagnosed with GEN-FGMLs were included in this study. H&E-stained slides were reviewed and clinicopathological parameters were recorded. Immunohistochemical staining was conducted for MUC2, MUC5AC, MUC6, CD10, CD56, synaptophysin, chromograninA, p53, Ki67, pepsinogen-I, H /K -ATPase and Desmin. The patients' ages ranged from 42 to 79 years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between OGA, GA-FG, and GA-FGM. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. These cells resembled fundic gland cells. None of the OGA invaded the submucosal layer. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Non-atrophic gastritis was observed in more than half of the background mucosa. All cases were diffusely positive for MUC6 and pepsinogen-I on immunohistochemistry. H /K -ATPase staining was negative or showed a scattered pattern in most cases. MUC5AC was expressed on the surface of GA-FGMs. p53 was focally expressed and the Ki67 index was low (1%-20%). Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view ( < 0.05) and had larger sizes ( < 0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA ( < 0.0001). Specimens with Ki-67 proliferation indices >2.5% and size >4.5 mm are more likely to be diagnosed with GA-FG and GA-FGM than OGA. GEN-FGMLs are group of well-differentiated gastric tumors with favourable biological behaviours, low cellular atypia, and low proliferation. Immunohistochemistry is critical for confirming diagnosis. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. Pathologists and endoscopists should be cautious to prevent misdiagnosis and overtreatment, especially in biopsy specimens.

High sugar content in peanut seeds is one of the major breeding objectives for peanut flavor improvement. In order to explore the genetic control of sugar accumulation in peanut kernels, we constructed a recombinant inbred line population of 256 F 2:6-7 lines derived from the Luhua11 × 06B16 cross. A high-resolution genetic map was constructed with 3692 bin markers through whole genome re-sequencing. The total map distance was 981.65 cM and the average bin marker distance was 0.27cM. A major stable QTL region ( qSCB09 / qSSCB09 ) was identified on linkage group (LG) B09 associated with both sucrose content (SC) and soluble sugar content (SSC) explaining 21.51-33.58% phenotypic variations. This major QTL region was consistently detected in three environments and mapped within a physical interval of 1.56 Mb on chromosome B09, and six candidate genes were identified. These results provide valuable information for further map-based cloning of favorable allele for sugar content in peanut.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by significant heterogeneity. We conducted a multi-omics integrated clustering analysis to categorize PDAC molecular subtypes. Multi-omics data from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) were integrated using ten clustering algorithms. Comparisons across PDAC subtypes were performed regarding prognosis, gene mutations, pathways, tumor microenvironment (TME), and chemotherapy sensitivity. A prognostic model was constructed utilizing Cox and Lasso regression based on subtype-related genes. Samples from the TCGA-PAAD cohort were classified into two subtypes. The CS1 subtype was identified as a high-risk, immunosilent subtype, while the CS2 subtype was characterized as a low-risk, immunoactive subtype. Compared to CS2 subtype, CS1 subtype exhibited shorter survival, higher frequency of genetic mutations, more aggressive tumor-promoting nature, lower TME immune score, and increased sensitivity to chemotherapy. The prognostic model related to PDAC subtypes displayed robust predictive efficiency; IL20RB gene emerged having superior predictive capability. We successfully identified two distinct PDAC subtypes. The developed prognostic model exhibited strong predictive efficacy; and the upregulation of IL20RB was identified as a promising therapeutic target for PDAC.

Given that microbiological analysis can be an alternative method that overcomes the shortcomings of traditional forensic technology, and skin samples may be the most common source of cases, the analysis of skin microbiome was investigated in this study. High-throughput sequencing targeting the V3-V4 region of 16S rRNA gene was performed to reveal the skin microbiome of healthy individuals in Guangdong Han. The bacterial diversity of the palm, navel, groin and plantar of the same individual was analyzed. The overall classification based on 16S rRNA gene amplicons revealed that the microbial composition of skin samples from different anatomical parts was different, and the dominant bacterial genus of the navel, plantar, groin and palm skin were dominated by Cutibacterium, Staphylococcus, Corynebacterium and Staphylococcus, respectively. PCoA analysis showed that the skin at these four anatomical locations could only be grouped into three clusters. A predictive model based on random forest algorithm showed the potential to accurately distinguish these four anatomical locations, which indicated that specific bacteria with low abundance were the key taxa. In addition, the skin microbiome in this study is significantly different from the dominant microbiome in saliva and vaginal secretions identified in our previous study, and can be distinguished from these two tissue fluids. In conclusion, the present findings on the community and microbial structure details of the human skin may reveal its potential application value in assessing the location of skin samples and the type of body fluids in forensic medicine. •In this study, four skin sites showed differences in the abundance of dominant flora and specific low-abundance bacteria.•The random forest model showed high accuracy in distinguishing skin locations of four different anatomical structures.•Microbial composition of skin, saliva and vaginal secretions varies widely for inferring forensic tissue fluid types.