Exploring the therapeutic potential of diterpenes in gastric cancer: Mechanisms, efficacy, and clinical prospects.

Gastric cancer (GC) remains a significant global health challenge, particularly prevalent in East Asia. Despite advancements in various treatment modalities, the prognosis for patients, especially those in advanced stages, remains poor, highlighting the need for innovative therapeutic approaches. This review explores the promising potential of diterpenes, naturally occurring compounds with robust anticancer properties, derived from diverse sources such as plants, marine organisms, and fungi. Diterpenes have shown the ability to influence reactive oxygen species (ROS) generation, ferroptosis, and autophagy, positioning them as attractive candidates for novel cancer therapies. This review explores the mechanisms of action of diterpenes and their clinical implications for the treatment of GC. Additionally, it addresses the challenges in translating these compounds from preclinical studies to clinical applications, emphasizing the need for further research to enhance their therapeutic profiles and minimize potential side effects. The discussion underscores the importance of diterpenes in future anticancer strategies, particularly in the fight against gastric cancer.

Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways.

This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe2+, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.

AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?

Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, immune escape, and other factors, the efficacy of tumor immunotherapy has been limited with its application to very small population size. Energy metabolism not only affects tumor progression but also plays a crucial role in immune escape. Tumor cells are more metabolically active and need more energy and nutrients to maintain their growth, which causes the surrounding immune cells to lack glucose, oxygen, and other nutrients, with the result of decreased immune cell activity and increased immunosuppressive cells. On the other hand, immune cells need to utilize multiple metabolic pathways, for instance, cellular respiration, and oxidative phosphorylation pathways to maintain their activity and normal function. Studies have shown that there is a significant difference in the energy expenditure of immune cells in the resting and activated states. Notably, competitive uptake of glucose is the main cause of impaired T cell function. Conversely, glutamine competition often affects the activation of most immune cells and the transformation of CD4+T cells into inflammatory subtypes. Excessive metabolite lactate often impairs the function of NK cells. Furthermore, the metabolite PGE2 also often inhibits the immune response by inhibiting Th1 differentiation, B cell function, and T cell activation. Additionally, the transformation of tumor-suppressive M1 macrophages into cancer-promoting M2 macrophages is influenced by energy metabolism. Therefore, energy metabolism is a vital factor and component involved in the reconstruction of the tumor immune microenvironment. Noteworthy and vital is that not only does the metabolic program of tumor cells affect the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their own functions, ultimately leading to changes in tumor immune function. Metabolic intervention can not only improve the response of immune cells to tumors, but also increase the immunogenicity of tumors, thereby expanding the population who benefit from immunotherapy. Consequently, identifying metabolic crosstalk molecules that link tumor energy metabolism and immune microenvironment would be a promising anti-tumor immune strategy. AMPK (AMP-activated protein kinase) is a ubiquitous serine/threonine kinase in eukaryotes, serving as the central regulator of metabolic pathways. The sequential activation of AMPK and its associated signaling cascades profoundly impacts the dynamic alterations in tumor cell bioenergetics. By modulating energy metabolism and inflammatory responses, AMPK exerts significant influence on tumor cell development, while also playing a pivotal role in tumor immunotherapy by regulating immune cell activity and function. Furthermore, AMPK-mediated inflammatory response facilitates the recruitment of immune cells to the tumor microenvironment (TIME), thereby impeding tumorigenesis, progression, and metastasis. AMPK, as the link between cell energy homeostasis, tumor bioenergetics, and anti-tumor immunity, will have a significant impact on the treatment and management of oncology patients. That being summarized, the main objective of this review is to pinpoint the efficacy of tumor immunotherapy by regulating the energy metabolism of the tumor immune microenvironment and to provide guidance for the development of new immunotherapy strategies.

Molecular mechanism underlying epithelial-mesenchymal transformation and cisplatin resistance in esophageal squamous cell carcinoma.

Esophageal cancer (EC) occupies the seventh spot of the most prevalent malignancy cancer ailments worldwide and the sixth leading cause of cancer-related death. Esophageal squamous cell carcinoma (ESCC) is also the most predominant histological subtype of EC, and cisplatin (DDP) is commonly used as a first-line chemotherapeutic drug for the late advanced stages of the disease. However, the emergence of drug resistance during clinical treatment possesses a significant challenge to the therapeutic success and patient outcomes. Collectively, the epithelial-mesenchymal transformation (EMT) is a process in which transcription factors are induced to regulate the expression of epithelial and stromal markers to promote the differentiation of epithelial cells into stromal cells. Recent studies have demonstrated a close association between EMT and chemotherapy resistance in tumor cells, with concrete evidence of reciprocal reinforcement. Therefore, in this review, we elucidate the molecular mechanism underlying ESCC, shed light on the mechanisms driving DDP resistance, and provide insights into the intricate interplay between EMT and ESCC. We have aimed to provide some new hypotheses and perspectives that may address-inform future therapeutic strategies for ESCC treatment.

The 3'­untranslated region of XB130 regulates its mRNA stability and translational efficiency in non­small cell lung cancer cells.

Silencing XB130 inhibits cell proliferation and epithelial-mesenchymal transition in non-small cell lung cancer (NSCLC), suggesting that downregulating XB130 expression may impede NSCLC progression. However, the molecular mechanism underlying the regulation of XB130 expression remains unclear. In the present study, the role of the 3'-untranslated region (3'-UTR) in the regulation of XB130 expression was investigated. Recombinant psiCHECK-2 vectors with wild-type, truncated, or mutant XB130 3'-UTR were constructed, and the effects of these insertions on reporter gene expression were examined using a dual-luciferase reporter assay and reverse transcription-quantitative PCR. Additionally, candidate proteins that regulated XB130 expression by binding to critical regions of the XB130 3'-UTR were screened for using an RNA pull-down assay, followed by mass spectrometry and western blotting. The results revealed that insertion of the entire XB130 3'-UTR (1,218 bp) enhanced reporter gene expression. Positive regulatory elements were primarily found in nucleotides 113-989 of the 3'-UTR, while negative regulatory elements were found in the 1-112 and 990-1,218 regions of the 3'-UTR. Deletion analyses identified nucleotides 113-230 and 503-660 of the 3'-UTR as two major fragments that likely promote XB130 expression by increasing mRNA stability and translation rate. Additionally, a U-rich element in the 970-1,053 region of the 3'-UTR was identified as a negative regulatory element that inhibited XB130 expression by suppressing translation. Furthermore, seven candidate proteins that potentially regulated XB130 expression by binding to the 113-230, 503-660, and 970-1,053 regions of the 3'-UTR were identified, shedding light on the regulatory mechanism of XB130 expression. Collectively, these results suggested that complex sequence integrations in the mRNA 3'-UTR variably affected XB130 expression in NSCLC cells.

HnRNPAB is an independent prognostic factor in non­small cell lung cancer and is involved in cell proliferation and metastasis.

Heterogeneous nuclear ribonucleoprotein A/B (hnRNPAB) is an RNA binding protein that is closely associated with the biological function and metabolism of RNA, which is involved in the malignant transformation of various tumor cells. However, the role and mechanisms of hnRNPAB in non-small cell lung cancer (NSCLC) are still unclear. In the present study, the expression levels of hnRNPAB in NSCLC and normal tissues were analyzed using the human protein atlas database and UALCAN database. The clinical significance of hnRNPAB was assayed using the data of NSCLC cases from The Cancer Genome Atlas database. Subsequently, two stable NSCLC cell lines with hnRNPAB knockdown were constructed and the effects of hnRNPAB silencing on cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) were identified. Genes associated with hnRNPAB expression in NSCLC were screened using the Linked Omics database and verified by quantitative real-time PCR (RT-qPCR). The database analysis indicated that hnRNPAB was mainly expressed in the nucleus of NSCLC cells. Compared with the normal tissues, hnRNPAB expression was overexpressed in NSCLC tissues and was closely associated with the overall survival, sex, tumor-node-metastases classification, and poor prognosis of patients with lung adenocarcinoma. Functionally, knockdown of hnRNPAB inhibited the proliferation, migration, invasion and EMT of NSCLC cells and arrested the cell cycle at G1 phase. Mechanistically, the bioinformatics analysis and RT-qPCR verification demonstrated that hnRNPAB knockdown led to a significant expression change of genes associated with tumorigenesis. In conclusion, the present study indicated that hnRNPAB played an important role in the malignant transformation of NSCLC, supporting the significance of hnRNPAB as a novel potential therapeutic target for the early diagnosis and prognosis of NSCLC.

Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors.

The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.

Epithelial-Mesenchymal Transition Gene Signature Is Associated with Neoadjuvant Chemoradiotherapy Resistance and Prognosis of Esophageal Squamous Cell Carcinoma.

Background: Neoadjuvant chemoradiotherapy (neo-CRT) in combination with surgery increases survival compared to surgery alone, as indicated by the esophageal squamous cell carcinoma (ESCC) treatment recommendations. However, the benefits of neo-CRT are diverse among patients. Consequently, the development of new biomarkers that correlate with neo-CRT might be important for the treatment of ESCC. Methods: The differentially expressed genes (DEG) between responsive and resistant samples from the GSE45670 dataset were obtained. On the TCGA dataset, survival analysis was performed to identify prognosis-related-EMT-genes. For EMT score model construction, lasso regression analysis in the TCGA cohort was used to identify the genes. In the TCGA-ESCC cohort, age, stage, and EMT score were used to construct a nomogram. Results: In total, 10 prognosis-related-EMT-genes were obtained. These 10 genes consisted of 6 risky genes and 4 protective genes. Based on the lasso analysis and univariate Cox regression, an EMT score model consisting of 7 genes (CLEC18A, PIR, KCNN4, MST1R, CAPG, ALDH5A1, and COX7B) was identified. ESCC patients with a high EMT score have a worse prognosis. These genes were differentially expressed between responsive and resistant patients and had a high accuracy for distinguishing resistant and responsive patients. Conclusions: The identified genes have the potential to function as molecular biomarkers for predicting ESCC patients' resistance to neo-CRT. This research may aid in the elucidation of the molecular processes driving resistance and the identification of targets for improving the prognosis for ESCC.

Association between eight hypermethylation-related genes and gastric cancer: a systematic review and meta-analysis.

Background: Although multiple gene promoter hypermethylation has been associated with gastric carcinogenesis, data on their specific relationship remains scant. We aimed to investigate the correlation between the status of multiple gene promoter methylation and gastric cancer (GC). Methods: We searched PubMed, EMBASE, CNKI, Wanfang, Cqvip and Cochrane Library up to May 2021. We systematically assessed the association between methylation status of the CpG islands and the risk of GC. We compared the incidence of DNA methylation between tumor and non-tumor tissues, and evaluated the clinicopathological significance of the DNA methylation in gastric carcinoma. The data was presented by an odds ratio (OR) with an accompanying 95% confidence interval (CI). We then generated forest plots calculated by fixed-effects or random-effects model. Results: This study enrolled a total of 201 studies (140 papers). Our analysis showed a higher frequency of methylation of the CpG islands in GC tissues compared to non-neoplastic tissues. Besides, the data demonstrated that polygene's aberrant promoter methylation might be linked to the initial development and progression of GC. Discussion: The genes with altered DNA methylation might serve as epigenetic biomarkers, providing a promising molecular diagnostic and prognostic tool for human GC. However, our findings need further evaluation in large randomized controlled trials.

Serum gamma-glutamyl transpeptidase-to-platelet ratio (GPR) can predict the prognosis of hepatocellular carcinoma: a meta-analysis and systematic review.

Background: The relationship between serum gamma-glutamyl transpeptidase-to-platelet ratio (GPR) before treatment and the prognosis of patients with hepatocellular carcinoma (HCC) is unclear. Here, we review and summarize existing data and try to determine the predictive value of GPR in the treatment of HCC. Methods: We searched Web of Science, PubMed, Embase and China national knowledge infrastructure (CNKI) for clinical trials investigating GPR and HCC in participants with and without HCC. We developed the inclusion criteria based on the principle of population-intervention-result-control-study design. Studies that do not meet the standards were excluded. Studies were subjected to quality assessments using the Cochrane Risk of Bias Tool for cluster-randomized control trials. Sensitivity, statistical, heterogeneity, and publication bias analyses on STATA version 16.1 (STATA 2020). Results: The pooled data from 7 studies of 1,952 patients showed that the specificity of GPR for predicting the prognosis of HCC was 0.67 (95% CI: 0.61-0.73), and the sensitivity was 0.62 (95% CI: 0.57-0.67). The Fagan chart prediction shows that the patient's GPR indicates the prognostic effect of HCC. The positive predictive value is 32%, which is significantly higher than before. The ROC curve is used to analyze the effectiveness of GPR in predicting the prognosis of HCC, and the area under the curve (AUC) is 0.69 (0.65-0.73). There is no publication bias in this study (The Deek funnel chart, P=0.48). Discussion: Our results are similar to those of most previous studies, and meta-analysis showed that GPR has well sensitivity, accuracy, and prognostic value in HCC.

Photodynamic Therapy in Combination with Chemotherapy, Targeted, and Immunotherapy As a Successful Therapeutic Approach for Advanced Gastric Adenocarcinoma: A Case Report and Literature Review.

Objective: To explore the efficacy of photodynamic therapy combined with chemotherapy, targeted therapy, and immunotherapy in poorly differentiated gastric adenocarcinoma (GAC). Background: Advanced GAC has high malignancy and mortality rate. To date, no study has applied photodynamic treatment (PDT) combined with chemo-, targeted, and immunotherapy to treat this cancer. Patient and methods: Clinical data of a patient diagnosed with poorly differentiated GAC admitted to the department of oncology of the Lanzhou University Second Hospital were retrospectively analyzed. The patient underwent four PDT procedures combined with chemo-, targeted, and immunotherapy. Results: A 72-year-old male patient received combination therapy of PDT. This treatment resolved the cancerous tissues and levels of tumor markers. There was no recurrence and metastasis during a 7-month follow-up. Conclusions: Combination therapy of PDT can effectively treat tumors and may be a method suitable for elderly patients with advanced GAC.

A comprehensive study of celastrol metabolism in vivo and in vitro using ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry.

Celastrol has attracted great attention owing to its anti-arthritis, antioxidant, and anticancer activities. Nevertheless, its metabolism in vivo (rats) and in vitro (rat liver microsomes and intestinal flora) has not been comprehensively characterized. In this study, ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry was used as a rapid and sensitive approach for studying the metabolism of celastrol in vivo and in vitro. A total of 43 metabolites were identified and characterized. These include 26 metabolites in vivo, and 28 metabolites in vitro (nine metabolites in rat liver microsomes and 24 metabolites in rat intestinal flora). Additionally, the celastrol-biotransformation capacity of the intestinal tract was confirmed to exceed that of the liver. Furthermore, the metabolic profile of celastrol is summarised. The information obtained from this study may provide a basis for understanding the pharmacological mechanisms of celastrol and will be beneficial for clinical applications.

The Role of N6-Methyladenosine Methylation in the Progression of Endometrial Cancer.

Purpose: N6-methyladenosine (m6A) methylation was the most abundant internal modification on messenger RNAs in eukaryotes. This study intended to explore the role of m6A methylation in endometrial cancer (EC). Materials and Methods: The m6A-sequencing data "GSE93911" of human EC were downloaded from Gene Expression Omnibus database. Hisat2 software and MACS2 were used to perform the alignment of reads and m6A methylation peak calling, and the peaks were annotated using Chipseeker. Then, differential m6A methylation peaks between normal and tumor samples were analyzed, followed by the functional enrichment analysis of the differentially methylated genes in promoter and 3' untranslated region (UTR) using Clusterprofiler. Based on the 450K methylated chip data, gene expression and clinical data in The Cancer Genome Atlas, the differentially methylated genes were verified, followed by Cox univariate/multivariate regression analysis and survival analysis. Finally, a risk prognosis model was constructed. Results: The m6A peak number was decreased in EC. The distribution of m6A peaks was highly enriched near transcriptional start site, in promoter, UTR, intron and exon, followed by distal intergenic. A total of 581 differentially methylated genes (361 hyper- and 220 hypomethylated genes) were identified in promoter and UTR regions that were enriched in insulin resistance (IR) and extracellular matrix (ECM). A total of 181 genes with significant differential expressions and differential methylation site in EC were selected. Of which, 31 genes were correlated with survival, and an 11-gene risk prognosis model was identified, including GDF7, BNC2, SLC8A1, B4GALNT3, DHCR24, ESRP1, HOXB9, IGSF9, KIAA1324, MSnX1, and PHGDH. Conclusion: The m6A methylation regulated EC progression by targeting the genes related to IR and ECM. A 11-gene risk prognosis model was identified to predict survival of patients with EC.

A Smart "Sense-and-Treat" Nanoplatform Based on Semiconducting Polymer Nanoparticles for Precise Photothermal-Photodynamic Combined Therapy.

Integrated theranostic nanoplatforms with biomarker recognition and photothermal- and photodynamic (PTT/PDT) therapy is in high demand but remains challenging. Herein, a "sense-and-treat" nanoplatform based on semiconducting polymer nanoparticles (SPNs) for ratiometric bioimaging of phospholipase D (PLD) activity and PTT/PDT combined therapy was proposed. Semiconducting polymer nanoparticles (PSBTBT NPs) serve not only as photothermal agents but also as fluorescent quenchers of Rhodamine B (Rhod B) through a PLD-cleavable linker. Chlorin e6 (Ce6) was used as a photodynamic agent and fluorescence reference. The obtained nanoplatform (PSBTBT-Ce6@Rhod NPs) showed high PDT efficiency and photothermal performance upon single laser irradiation. The PTT/PDT combined therapy achieved more efficient tumor inhibition results as compared with single treatments. In addition, the overexpressed biomarker PLD in tumor tissue will cleave Rhod, leading to the fluorescence recovery of Rhod B and thus allowing the activatable fluorescence imaging of tumor and targeted phototherapy.

The self-assembly of a hybrid photosensitizer for the synergistically enhanced photodynamic/photothermal therapy.

The simultaneous near-infrared (NIR)-absorbed photodynamic therapy (PDT)/photothermal therapy (PTT) has proved to be a promising approach to increase the antitumor efficiency due to their synergistic effect. Herein, a boron dipyrromethene (BODIPY)-based photosensitizer was designed and synthesized for the enhanced synergistic NIR-absorbed PDT/PTT therapy upon NIR light irradiation. In this strategy, a three-dimensional rigid polyhedral oligomeric silsesquioxane (POSS) block was introduced into the Br-BODIPY molecule to alleviate the aggregation of the photosensitizer. The POSS hybrid BODIPY (Br-BODIPY-POSS) was further functionalized with a biocompatible amphiphilic PEG via a facile thiol-ene "click" reaction, affording Br-BODIPY-POSS-PEG2000 (BBPP). BBPP can self-assemble into nanoparticles, which maintain a competitive photothermal conversion efficiency (ηBBPP = 30.2%) with its counterpart Br-BODIPY-PEG (BBP, ηBBP = 34.5%). Significantly, BBPP exhibited a relatively higher oxygen quantum yield (ΦBBPP = 0.405) than BBP (ΦBBP = 0.175). The in vitro and in vivo experiments showed that BBPP possessed negligible dark cytotoxicity and a better phototherapeutic outcome than BBP. The proof-of-concept of the POSS hybrid photosensitizer offers guidance for the construction of single-component and PDT/PTT-balanced NIR nanoagents to promote the cancer therapeutic efficacy in the future.

Members of the miR-30 family inhibit the epithelial-to-mesenchymal transition of non-small-cell lung cancer cells by suppressing XB130 expression levels.

MicroRNAs (miRs) are associated with cancer metastasis. Aberrant expression levels of members of the miR-30 family have been observed in non-small-cell lung cancer (NSCLC). However, the effects of miR-30 family members on the epithelial-to-mesenchymal transition (EMT) of NSCLC cells and the underlying molecular mechanisms have not yet been fully elucidated. The present study investigated the effects of miR-30 family members on EMT, migration and invasion of NSCLC cells and found that overexpression of these miRs inhibited EMT via decreasing the expression levels of N-cadherin, ß-catenin and SNAI1, along with weakened migration and invasion abilities. Then, XB130 was identified as a downstream target of the miR-30 family members. XB130-knockdown also inhibited EMT of NSCLC cells, whereas ectopic overexpression of XB130 partly rescued the suppressive effects of miR-30c and miR-30d on EMT. In conclusion, miR-30 family members inhibited EMT of NSCLC cells, partially via suppressing XB130 expression levels.

Preparation and antitumor evaluation of hinokiflavone hybrid micelles with mitochondria targeted for lung adenocarcinoma treatment.

Hinokiflavone (HF) is a natural biflavonoid extracted from medicinal plants such as Selaginella tamariscina and Platycladus orientalis. HF plays a crucial role in the treatment of several cancers. However, its poor solubility, instability, and low bioavailability have limited its use. In this study, soluplus/d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS)/dequalinium (DQA) was applied to improve the solubilization efficiency and stability of HF. HF hybrid micelles were prepared via thin-film hydration method. The physicochemical properties of micelles, including particle size, zeta potential, encapsulation efficiency, drug loading, CMC value, and stability were investigated. The in vitro cytotoxicity assay showed that the cytotoxicity of the HF hybrid micelles was higher than that of free HF. In addition, the HF hybrid micelles improved anticancer efficacy and induced mitochondria-mediated apoptosis, which is associated with the high levels of ROS inducing decreased mitochondrial membrane potential, promoting apoptosis of tumor cells. Furthermore, in vivo tumor suppression, smaller tumor volume and increased expression of pro-apoptotic proteins were found in nude mice treated with HF hybrid micelles, suggesting that HF hybrid micelles had stronger tumor suppressive activity compared with free HF. In summary, HF hybrid micelles developed in this study enhanced antitumor effect, which may be a potential drug delivery system for the treatment of lung adenocarcinoma.

XB130, regulated by miR-203, miR-219, and miR-4782-3p, mediates the proliferation and metastasis of non-small-cell lung cancer cells.

XB130 is a novel adapter protein that behaves as a tumor promoter or suppressor mediating cell proliferation and metastasis in the development of different human tumors. Altered expression of XB130 has been verified in human non-small cell-lung cancer (NSCLC). However, the exact effect of XB130 on NSCLC is not well-understood. In this study, we investigated the biological function and posttranscriptional regulation of XB130 in NSCLC. First, the effects of XB130 silence on NSCLC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were examined. Then the targeting relationship between XB130 and miR-203, miR-219, or miR-4782-3p was demonstrated by dual-luciferase reporter assay. Finally, the effects of miR-203, miR-219, and miR-4782-3p on NSCLC cell function were studied, respectively. We found that XB130 silence significantly inhibited cell growth, migration and invasion, and reversed EMT. Furthermore, XB130 was posttranscriptionally regulated by miR-203, miR-219, and miR-4782-3p. Overexpression of miR-203, miR-219, or miR-4782-3p inhibited cell growth, migration and invasion, and reversed EMT, just like the role of XB130 in NSCLC cells, whereas the suppressive effects of microRNA (miRNA) overexpression were weakened by miRNA inhibitors or ectopic expression of XB130 in NSCLC cells. These data demonstrate that XB130 is posttranscriptionally regulated by miR-203, miR-219, and miR-4782-3p and mediates the proliferation and metastasis of NSCLC cells.

UHPLC-Q-TOF-MS/MS method based on four-step strategy for metabolites of hinokiflavone in vivo and in vitro.

Hinokiflavone (HF), belonging to biflavonoids, possesses excellent pharmacological activities, including anti-inflammatory, antioxidant and antitumor activity. Nevertheless, its metabolism in vivo (rats) and in vitro (rat liver microsomes and intestinal flora) is presently not characterized. In this study, ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) based on four-step strategy was a rapid method for the detection of HF metabolites. A total of 41 metabolites in vivo, 49 metabolites in vitro were characterized. It also verified that intestinal tract exceeds the liver in the biotransformation of HF. More significant, the main metabolic pathways for HF were mainly bio-transformed to various mono-flavone resulting from the rupture of connective CO bonds, which exhibited a large distinction with other biflavones. Noteworthily, glutamine conjugation and glycine conjugation were considered as unique metabolic pathways of HF. The information obtained from this study contributes to better understanding of pharmacological mechanism of HF.