Potential applications of dual haptoglobin expression in the reclassification and treatment of hepatocellular carcinoma.

HCC is a malignancy characterized by high incidence and mortality rates. Traditional classifications of HCC primarily rely on tumor morphology, phenotype, and multicellular molecular levels, which may not accurately capture the cellular heterogeneity within the tumor. This study integrates scRNA-seq and bulk RNA-seq to spotlight HP as a critical gene within a subgroup of HCC malignant cells. HP is highly expressed in HCC malignant cells and lowly expressed in T cells. Within malignant cells, elevated HP expression interacts with C3, promoting Th1-type responses via the C3/C3AR1 axis. In T cells, down-regulating HP expression favors the expression of Th1 cell-associated marker genes, potentially enhancing Th1-type responses. Consequently, we developed a "HP-promoted Th1 response reclassification" gene set, correlating higher activity scores with improved survival rates in HCC patients. Additionally, four predictive models for neoadjuvant treatment based on HP and C3 expression were established: 1) Low HP and C3 expression with high Th2 cell infiltration; 2) High HP and low C3 expression with high Th2 cell infiltration; 3) High HP and C3 expression with high Th1 cell infiltration; 4) Low HP and high C3 expression with high Th1 cell infiltration. In conclusion, the HP gene selected from the HCC malignant cell subgroup (Malignant_Sub 6) might serve as a potential ally against the tumor by promoting Th1-type immune responses. The establishment of the "HP-promoted Th1 response reclassification" gene set offers predictive insights for HCC patient survival prognosis and neoadjuvant treatment efficacy, providing directions for clinical treatments.

SmEIL1 transcription factor inhibits tanshinone accumulation in response to ethylene signaling in Salvia miltiorrhiza.

Among the bioactive compounds, lipid-soluble tanshinone is present in Salvia miltiorrhiza, a medicinal plant species. While it is known that ethephon has the ability to inhibit the tanshinones biosynthesis in the S. miltiorrhiza hairy root, however the underlying regulatory mechanism remains obscure. In this study, using the transcriptome dataset of the S. miltiorrhiza hairy root induced by ethephon, an ethylene-responsive transcriptional factor EIN3-like 1 (SmEIL1) was identified. The SmEIL1 protein was found to be localized in the nuclei, and confirmed by the transient transformation observed in tobacco leaves. The overexpression of SmEIL1 was able to inhibit the tanshinones accumulation to a large degree, as well as down-regulate tanshinones biosynthetic genes including SmGGPPS1, SmHMGR1, SmHMGS1, SmCPS1, SmKSL1 and SmCYP76AH1. These are well recognized participants in the tanshinones biosynthesis pathway. Further investigation on the SmEIL1 was observed to inhibit the transcription of the CPS1 gene by the Dual-Luciferase (Dual-LUC) and yeast one-hybrid (Y1H) assays. The data in this work will be of value regarding the involvement of EILs in regulating the biosynthesis of tanshinones and lay the foundation for the metabolic engineering of bioactive ingredients in S. miltiorrhiza.

Bioactive compounds and biological functions of medicinal plant-derived extracellular vesicles.

Extracellular vesicles (EVs) are tiny lipid bilayer-enclosed membrane particles released from a variety of cell types into the surrounding environment. These EVs have massive participated in cell-to-cell communication and interspecies communication. In recent years, plant-derived extracellular vesicles (PDEVs) and "exosome-like" EVs populations found in distinct plants have attracted widespread attention. Especially, research on medicinal plant-derived extracellular vesicles (MPDEVs) are increasing, which are considered a kind of promising natural compound. This review summarizes current knowledge on MPDEVs in terms of bioactive compounds, including small RNA, protein, lipid, and metabolite, have been found on the surface and/or in the lumen of MPDEVs. Moreover, both in vitro and in vivo experiments have shown that MPDEVs exert broad biomedical functions, such as anti-inflammatory, anticancer, antioxidant, modulate microbiota, etc. MPDEVs may be a better substitute than animal-derived extracellular vesicles (ADEVs) because of safety and biocompatibility in the future.

Chemical profiling and investigation of molecular mechanisms underlying anti-hepatocellular carcinoma activity of extracts from Polygonum perfoliatum L.

Polygonum perfoliatum L. is an herbal medicine that has been extensively used in traditional Chinese medicine to treat various health conditions ranging from ancient internal to surgical and gynecological diseases. Numerous studies suggest that P. perfoliatum extract elicits significant anti-tumor, anti-inflammatory, anti-bacterial, and anti-viral effects. Nevertheless, the underlying mechanisms of its anti-liver cancer effects remain poorly understood. Our study suggests that P. perfoliatum stem extract (PPLA) has a favorable safety profile and exhibits a significant anti-liver cancer effect both in vitro and in vivo. We identified that PPLA activates the cGMP-PKG signaling pathway, and key regulatory genes including ADRA1B, PLCB2, PRKG2, CALML4, and GLO1 involved in this activation. Moreover, PPLA modulates the expression of genes responsible for the cell cycle. Additionally, we identified four constituents of PPLA, namely taxifolin, myricetin, eriodictyol, and pinocembrin, that plausibly act via the cGMP-PKG signaling pathway. Both in vitro and in vivo experiments confirmed that PPLA, along with its constituting compounds taxifolin, myricetin, and eriodictyol, exhibit potent anti-cancer activities and hold the promise of being developed into therapeutic agents.

Does each Component of Reactive Oxygen Species have a Dual Role in the Tumor Microenvironment?

Reactive oxygen species (ROS) are a class of highly reactive oxidizing molecules, including superoxide anion (O2•-) and hydrogen peroxide (H2O2), among others. Moderate levels of ROS play a crucial role in regulating cellular signaling and maintaining cellular functions. However, abnormal ROS levels or persistent oxidative stress can lead to changes in the tumor microenvironment (TME) that favor cancer development. This review provides an overview of ROS generation, structure, and properties, as well as their effects on various components of the TME. Contrary to previous studies, our findings reveal a dual effect of ROS on different components of the TME, whereby ROS can either enhance or inhibit certain factors, ultimately leading to the promotion or suppression of the TME. For example, H2O2 has dual effects on immune cells and non-cellular components within the TME, while O2•- has dual effects on T cells and fibroblasts. Furthermore, each component demonstrates distinct mechanisms of action and ranges of influence. In the final section of the article, we summarize the current clinical applications of ROS in cancer treatment and identify certain limitations associated with existing therapeutic approaches. Therefore, this review aims to provide a comprehensive understanding of ROS, highlighting their dual effects on different components of the TME, and exploring the potential clinical applications that may pave the way for future treatment and prevention strategies.

Contribution of PGAP3 co-amplified and co-overexpressed with ERBB2 at 17q12 involved poor prognosis in gastric cancer.

The locus at 17q12 erb-b2 receptor tyrosine kinase 2 (ERBB2) has been heavily amplificated and overexpressed in gastric cancer (GC), but it remains to be elucidated about the clinical significance of the co-amplification and co-overexpression of PGAP3 gene located around ERBB2 in GC. The profile of PGAP3 and ERBB2 in four GC cell lines and tissue microarrays containing 418 primary GC tissues was assessed to investigate the co-overexpression and clinical significance of the co-amplified genes, and to evaluate the impact of the co-amplified genes on the malignancy of GC. Co-amplification of PGAP3 and ERBB2 accompanied with co-overexpression was observed in a haploid chromosome 17 of NCI-N87 cells with double minutes (DMs). PGAP3 and ERBB2 were overexpressed and positively correlated in 418 GC patients. Co-overexpression of the PGAP3 and ERBB2 was correlated with T stage, TNM stage, tumour size, intestinal histological type and poor survival proportion in 141 GC patients. In vitro, knockdown of the endogenous PGAP3 or ERBB2 decreased cell proliferation and invasion, increased G1 phase accumulation and induced apoptosis in NCI-N87 cells. Furthermore, combined silencing of PGAP3 and ERBB2 showed an additive effect on resisting proliferation of NCI-N87 cells compared with targeting ERBB2 or PGAP3 alone. Taken together, the co-overexpression of PGAP3 and ERBB2 may be crucial due to its significant correlation with clinicopathological factors of GC. Haploid gain of PGAP3 co-amplified with ERBB2 is sufficient to facilitate the malignancy and progression of GC cells in a synergistic way.

Intercellular Communication Reveals Therapeutic Potential of Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer.

(1) Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity. The epithelial-mesenchymal transition (EMT) is one of the inducers of cancer metastasis and migration. However, the description of the EMT process in TNBC using single-cell RNA sequencing (scRNA-seq) remains unclear. (2) Methods: In this study, we analyzed 8938 cellular gene expression profiles from five TNBC patients. We first scored each malignant cell based on functional pathways to determine its EMT characteristics. Then, a pseudo-time trajectory analysis was employed to characterize the cell trajectories. Furthermore, CellChat was used to identify the cellular communications. (3) Results: We identified 888 epithelium-like and 846 mesenchyme-like malignant cells, respectively. A further pseudo-time trajectory analysis indicated the transition trends from epithelium-like to mesenchyme-like in malignant cells. To characterize the potential regulators of the EMT process, we identified 10 dysregulated transcription factors (TFs) between epithelium-like and mesenchyme-like malignant cells, in which overexpressed forkhead box protein A1 (FOXA1) was recognized as a poor prognosis marker of TNBC. Furthermore, we dissected the cell-cell communications via ligand-receptor (L-R) interactions. We observed that tumor-associated macrophages (TAMs) may support the invasion of malignant epithelial cells, based on CXCL-CXCR2 signaling. The tumor necrosis factor (TNF) signaling pathway secreted by TAMs was identified as an outgoing communication pattern, mediating the communications between monocytes/TAMs and malignant epithelial cells. Alternatively, the TNF-related ligand-receptor (L-R) pairs showed promising clinical implications. Some immunotherapy and anti-neoplastic drugs could interact with the L-R pairs as a potential strategy for the treatment of TNBC. In summary, this study enhances the understanding of the EMT process in the TNBC microenvironment, and dissections of EMT-related cell communications also provided us with potential treatment targets.

The potency of common proinflammatory cytokines measurement for revealing the risk and severity of anxiety and depression in psoriasis patients.

OBJECTIVE: Proinflammatory cytokines mediate anxiety and depression in various ways, such as immunity, inflammation, and the hypothalamic-pituitary-adrenal axis. This study intended to further explore the linkage of common proinflammatory cytokine levels with anxiety and depression in psoriasis patients. METHODS: Totally, 150 psoriasis patients and 50 healthy controls (HCs) were included; the serum samples were collected, then common proinflammatory cytokines were measured by ELISA. Hospital Anxiety and Depression Scale (HADS) was assessed. RESULTS: HADS-anxiety (HADS-A) score, HADS-depression (HADS-D) score, TNF-α, IL-1ß, IL-6, IL-12, IL-17A, and IL-23 were all increased in psoriasis patients compared to HCs (all p < 0.05). In psoriasis patients, TNF-α (p = 0.001), IL-12 (p = 0.035), and IL-17A (p < 0.001), but not IL-1ß (p = 0.255), IL-6 (p = 0.248), and IL-23 (p = 0.216), were positively linked to HADS-A score. Meanwhile, TNF-α (p = 0.007) and IL-17A (p = 0.007) were enhanced in psoriasis patients with anxiety in contrast to those without anxiety; whereas IL-1ß (p = 0.178), IL-6 (p = 0.360), IL-12 (p = 0.239), and IL-23 (p = 0.450) were not different. TNF-α (p < 0.001), IL-1ß (p = 0.013), Il-17A (p < 0.001), and IL-23 (p = 0.023), but not IL-6 (p = 0.143) and IL-12 (p = 0.158), were positively linked to HADS-D score. Concurrently, TNF-α (p = 0.015), IL-17A (p < 0.001), and IL-23 (p = 0.017) were climbed in psoriasis patients with depression by comparison to those without depression; whereas IL-1ß (p = 0.113), IL-6 (p = 0.237), IL-12 (p = 0.660) did not differ. CONCLUSION: TNF-α, IL-17A, and IL-23 increments reflect anabatic anxiety and depression in psoriasis patients, uncovering the potency of proinflammatory cytokines measurement for monitoring or even preventing psoriasis patients' anxiety and depression.

Decoding Immune Heterogeneity of Melanoma and identifying immune-prognostic hub genes.

Melanoma is an aggressive skin cancer that has gained attention worldwide. Growing evidence has highlighted that the tumor microenvironment (TME) is an important feature of carcinogenesis and contributes to therapeutic efficacy in melanoma. However, additional advances in melanoma immuno-oncology are necessary to achieve a comprehensive knowledge of the immune infiltrate population and to identify accurate and readily measurable biomarkers. In this study, we analyzed gene expression of 468 melanoma cases from the TCGA database, which led to the identification of three melanoma clusters (representedby low, median and high infiltration) that display unique immune features. We found that the microenvironment clusters had substantial prognostic efficacy. The median cluster was characterized by an inability to draw immune cells, highlighting possible immune escape mechanisms, and lower CXCL9 and CXCL10 expression, which was correlated to poor prognosis. Deep molecular characterization of immune cells, cytolytic-activity and tumor-inflammatory status revealed diversity of the local immune infiltration landscape in the melanoma clusters. Differentially expressed genes related to TME were extracted from each infiltration cluster. Functional annotations revealed that these genes were mainly related to immune system activation and the processes of immunoreaction. The top ten hub genes in immune infiltration-related protein-protein interaction (PPI) networks were selected for further prognostic investigation. Further validation showed that five of ten hub genes were good prognostic biomarkers for melanoma in two independent groups from the Gene Expression Omnibus database. In brief, these data highlight that systemic characterization of melanoma could uncover tumor infiltrate characteristics, which can help select the most adequate treatment and identify consistent and important indicators of the local immune tumor microenvironment in melanoma patients.

Synthesis of natural 3'-Prenylchalconaringenin and biological evaluation of ameliorating non-alcoholic fatty liver disease and metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and important risk factor for cardiac diseases, diabetes and extrahepatic cancers. Natural 3'-geranylchalconaringenin (GC) and desmethylxanthohumol (DX) from hop were synthesized using a regio-selective iodination and the Suzuki coupling reaction as key steps. GC and DX, along with their aglycone naringenin chalcone (NC) were investigated their decreasing the accumulation of cellular lipids. GC reduced lipid content and activated the AMP-activated protein kinase (AMPK) pathway in HepG2 and 3T3-L1 cells. In addition, GC had an obvious therapeutic effect on alleviating NAFLD and metabolic syndrome by activating the AMPK pathway in vivo. In conclusion, GC may be potentially used as a candidate drug and functional food for treating NAFLD and metabolic syndrome.

A New Risk Polymorphism rs10403848 of CARD8 Significantly Associated with Psoriasis Vulgaris in Northeastern China.

Caspase recruitment domain family member 8 (CARD8) is an adaptor molecule that negatively regulates nuclear factor-κB (NF-κB) activation, interleukin (IL)-1ß secretion, and apoptosis. These play important roles in the pathogenesis of psoriasis. Genetic variants of CARD8 have been associated with an increased risk of several inflammatory diseases and psoriasis in Europe. However, nothing is known about the association of the polymorphisms of CARD8 and psoriasis vulgaris (PsV) in the Han population of northeastern China. To investigate the potential association between them, we designed a case-control study to genotype four selected single nucleotide polymorphisms (SNPs) using the improved multiplex ligation reaction (iMLDR) method. Model-based single SNP frequentist-test and haplotype association studies were performed to assess the association between SNPs and PsV. The results showed that the intron SNP rs10403848 was significantly associated with PsV (additive model p=0.0418, p'=0.0411, and statistical power 0.1902; heterozygous model p=0.0418, p'=0.0164, and statistical power 0.9406). A potential risk locus of nonsynonymous SNP rs2043211 found in the European population did not show a significant association in our study. We found that the polymorphism rs10403848 in CARD8 is significantly associated with PsV risk in the Han population of northeastern China. CARD8 may be involved in PsV in this population, as in the European population, but a different genetic process should be considered for the heterogeneity of risk loci.

MiR-876-5p suppresses cell proliferation by targeting Angiopoietin-1 in the psoriasis.

Psoriasis is an autoimmune disease characterized by abnormal differentiation and hyper-proliferation of epidermal keratinocytes. The object of the study is to investigate the role of miRNA-876-5p in psoriasis. It reported that MicroRNAs (miRNAs) played roles in the malignant progression in psoriasis development. The expression of miR-876-5p was found to be down-regulated in psoriasic tissue and blood of patients. The luciferase assay verified the targeting role of miR-876-5p to 3'UTR of Angiopoietin-1 (Ang-1). Proliferation of psoriasic cells were inhibited by miR-876-5p and hold on G0/G1 phase. Further studies showed that miR-876-5p suppressed proliferation by restraining the expression of Ang-1, which would regulate the phosphorylation level of PI3K, AKT, mTOR and ERK in psoriasic cells. Invasion and adhesion, serving as important behavioral traits of epidermal keratinocytes cells, were suppressed by excessive miR-876-5p in psoriasic cells also. MiR-876-5p would be expected to be biomarker and potential therapeutic targets for the treatment of psoriasis.