HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). AIM: To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. METHODS: Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. RESULTS: In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. CONCLUSION: TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.

Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review.

The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

Erianin inhibits the progression of triple-negative breast cancer by suppressing SRC-mediated cholesterol metabolism.

Triple-negative breast cancer (TNBC) is highly malignant and lacks effective biotherapeutic targets. The development of efficient anticancer drugs with low toxicity and few side effects is a hotspot in TNBC treatment research. Although erianin is known to have potent antitumor activity, its regulatory mechanism and target in TNBC have not been fully elucidated, hampering further drug development. This study showed that erianin can significantly inhibit TNBC cell proliferation and migration, promote cell apoptosis, and inhibit the growth of transplanted tumors in mice. Mechanistically, through network pharmacology analysis, molecular docking and cellular thermal shift assays, we preliminarily identified SRC as the cellular target of erianin. Erianin potently inhibited the expression of SRC, which mediated the anticancer effect of erianin in TNBC. Moreover, erianin can downregulate the expression of genes related to cholesterol synthesis and uptake by targeting SRC, interfering with cholesterol levels in TNBC, thereby inhibiting the progression of TNBC in vivo and in vitro. Taken together, our results suggest that erianin may inhibit the progression of TNBC by suppressing SRC-mediated cholesterol metabolism, and erianin has the great potential to be an effective treatment for TNBC patients.

Dinuclear NHC-gold(I)-thiolato and -alkynyl complexes: synthesis, anticancer activity, and catalytic activity in lactonization reactions.

A series of novel dinuclear NHC-gold-thiolato and -alkynyl complexes bearing aromatic linkers were successfully synthesized by an efficient and simple synthetic route. The catalytic activity of these complexes was tested in a lactonization reaction. The reaction proceeds in high efficiency, in short reaction time and under mild conditions, and is complementary to existing methods. Furthermore, the digold(I)-thiolato derivatives exhibit remarkable cytotoxicity towards several cancer cell lines.

Erratum: [Corrigendum] Hydrogen gas post­conditioning alleviates cognitive dysfunction and anxiety­like behavior in a rat model of subarachnoid hemorrhage.

[This corrects the article DOI: 10.3892/etm.2021.10555.].

Fe3+-induced coordination cross-linking gallic acid-carboxymethyl cellulose self-healing hydrogel.

Self-healing hydrogel is a promising soft material for applications in wound dressings, drug delivery, tissue engineering, biomimetic electronic skin, and wearable electronic devices. However, it is a challenge to fabricate the self-healing hydrogels without external stimuli. Inspired by mussel, the metal-catechol complexes were introduced into the hydrogel systems to prepare the mussel-inspired hydrogels by regulating the gelation kinetics of Fe3+ crosslinkers with gallic acid (GA) in this research. The amine-functionalized carboxymethyl cellulose (CMC) was grafted with GA and then chelated with Fe3+ to form a multi-response system. The crosslinking of carboxymethyl cellulose-ethylenediamine-gallic acid (CEG) hydrogel was controlled by adjusting the pH to affect the iron coordination chemistry, which could enhance the self-healing properties and mechanical strength of hydrogels. In addition, the CEG hydrogel exhibited great antibacterial and antioxidant properties. And the CEG hydrogel could strongly adhere to the skin tissue. The adhesion strength of CEG hydrogel on pigskin was 11.44 kPa, which is higher than that of commercial wound dressings (∼5 kPa). Moreover, the thixotropy of the CEG hydrogel was confirmed with rheological test. In summary, it has great potential in the application field of wound dressing.

RuZn NPs with electroactivity and oxidase-like property for dual-mode anti-cancer drug monitoring.

6-mercaptopurine (6-MP) as the effective anti-cancer drug was used for the treatment of Crohn's disease and acute lymphoblastic leukaemia, but the response to maintenance therapy was variable with individual differences. In order to control the dosage and decrease the side effects of 6-MP, a sensitive and stable assay was urgently needed for 6-MP monitoring. Herein, RuZn NPs with electrochemical oxidation property and oxidase-like activity was proposed for dual-mode 6-MP monitoring. Burr-like RuZn NPs were prepared and explored to not only exhibit an electrochemical oxidation signal at 0.78 V, but also displayed excellent oxidase-like performances. RuZn NPs were utilized for the dual-mode monitoring of 6-MP, attributing to the formation of Ru-SH covalent bonding. The colorimetric method showed good linearity from 10 µM to 5 mM with the limit of detection (LOD) of 300 nM, while the electrochemical method provided a higher sensitivity with the LOD of 37 nM in range from 100 nM to 200 µM. This work provided a new way for the fabrication of dual-functional nanotags with electroactivity and oxidase-like property, and opened a dual-mode approach for the 6-MP detection applications with complementary and satisfactory results.

Quantification of MicroRNA in a Single Living Cell via Ionic Current Rectification-Based Nanopore for Triple Negative Breast Cancer Diagnosis.

Accurate analysis of microRNAs (miRNAs) at the single-cell level is extremely important for deeply understanding their multiple and intricate biological functions. Despite some advancements in analyzing single-cell miRNAs, challenges such as intracellular interferences and insufficient detection limits still remain. In this work, an ultrasensitive nanopore sensor for quantitative single-cell miRNA-155 detection is constructed based on ionic current rectification (ICR) coupled with enzyme-free catalytic hairpin assembly (CHA). Benefiting from the enzyme-free CHA amplification strategy, the detection limit of the nanopore sensor for miRNA-155 reaches 10 fM and the nanopore sensor is more adaptable to complex intracellular environments. With the nanopore sensor, the concentration of miRNA-155 in living single cells is quantified to realize the early diagnosis of triple-negative breast cancer (TNBC). Furthermore, the nanopore sensor can be applied in screening anticancer drugs by tracking the expression level of miRNA-155. This work provides an adaptive and universal method for quantitatively analyzing intracellular miRNAs, which will greatly improve our understanding of cell heterogeneity and provide a more reliable scientific basis for exploring major diseases at the single-cell level.

Identification of potential biomarkers for aging diagnosis of mesenchymal stem cells derived from the aged donors.

BACKGROUND: The clinical application of human bone-marrow derived mesenchymal stem cells (MSCs) for the treatment of refractory diseases has achieved remarkable results. However, there is a need for a systematic evaluation of the quality and safety of MSCs sourced from donors. In this study, we sought to assess one potential factor that might impact quality, namely the age of the donor. METHODS: We downloaded two data sets from each of two Gene Expression Omnibus (GEO), GSE39035 and GSE97311 databases, namely samples form young (< 65 years of age) and old (> 65) donor groups. Through, bioinformatics analysis and experimental validation to these retrieved data, we found that MSCs derived from aged donors can lead to differential expression of gene profiles compared with those from young donors, and potentially affect the function of MSCs, and may even induce malignant tumors. RESULTS: We identified a total of 337 differentially expressed genes (DEGs), including two upregulated and eight downregulated genes from the databases of both GSE39035 and GSE97311. We further identified 13 hub genes. Six of them, TBX15, IGF1, GATA2, PITX2, SNAI1 and VCAN, were highly expressed in many human malignancies in Human Protein Atlas database. In the MSCs in vitro senescent cell model, qPCR analysis validated that all six hub genes were highly expressed in senescent MSCs. Our findings confirm that aged donors of MSCs have a significant effect on gene expression profiles. The MSCs from old donors have the potential to cause a variety of malignancies. These TBX15, IGF1, GATA2, PITX2, SNAI1, VCAN genes could be used as potential biomarkers to diagnosis aging state of donor MSCs, and evaluate whether MSCs derived from an aged donor could be used for therapy in the clinic. Our findings provide a diagnostic basis for the clinical use of MSCs to treat a variety of diseases. CONCLUSIONS: Therefore, our findings not only provide guidance for the safe and standardized use of MSCs in the clinic for the treatment of various diseases, but also provide insights into the use of cell regeneration approaches to reverse aging and support rejuvenation.

HSP27 promotes vasculogenic mimicry formation in human salivary adenoid cystic carcinoma via the AKT-MMP-2/9 pathway.

PURPOSE: To explore the role and mechanism of heat shock protein 27 (HSP27) in SACC VM formation. STUDY DESIGN: Immunohistochemistry and double staining with cluster of differentiation 31 (CD31) and periodic acid-Schiff (PAS) were used to detect HSP27 expression and VM in 70 SACC tissue samples separately. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and immunofluorescence were used to detect gene and protein expression. HSP27 in SACC cells were overexpression or downregulated by transfecting HSP27 or short hairpin RNA target HSP27 (sh-HSP27). The migration and invasion abilities of SACC cells were detected using wound healing and Transwell invasion assays. The VM formation ability of the cells in vitro was detected using a Matrigel 3-dimensional culture. RESULTS: HSP27 expression was positively correlated with VM formation and affected the prognosis of patients. In vitro, HSP27 upregulation engendered VM formation and the invasion and migration of SACC cells. Mechanistically, HSP27 upregulation increased Akt phosphorylation and subsequently increased downstream matrix metalloproteinase 2 and 9 expressions. CONCLUSION: HSP27 may plays an important role in VM formation in SACC via the AKT-MMP-2/9 signalling pathway.

Local delivery of stem cell spheroids with protein/polyphenol self-assembling armor to improve myocardial infarction treatment via immunoprotection and immunoregulation.

Stem cell therapies have shown great potential for treating myocardial infarction (MI) but are limited by low cell survival and compromised functionality due to the harsh microenvironment at the disease site. Here, we presented a Mesenchymal stem cell (MSC) spheroid-based strategy for MI treatment by introducing a protein/polyphenol self-assembling armor coating on the surface of cell spheroids, which showed significantly enhanced therapeutic efficacy by actively manipulating the hostile pathological MI microenvironment and enabling versatile functionality, including protecting the donor cells from host immune clearance, remodeling the ROS microenvironment and stimulating MSC's pro-healing paracrine secretion. The underlying mechanism was elucidated, wherein the armor protected to prolong MSCs residence at MI site, and triggered paracrine stimulation of MSCs towards immunoregulation and angiogenesis through inducing hypoxia to provoke glycolysis in stem cells. Furthermore, local delivery of coated MSC spheroids in MI rat significantly alleviated local inflammation and subsequent fibrosis via mediation macrophage polarization towards pro-healing M2 phenotype and improved cardiac function. In general, this study provided critical insight into the enhanced therapeutic efficacy of stem cell spheroids coated with a multifunctional armor. It potentially opens up a new avenue for designing immunomodulatory treatment for MI via stem cell therapy empowered by functional biomaterials.

Optimization of benzene exposure risk assessment: An integrated approach utilizing internal and external concentrations with a focus on biomarkers S-PMA & t, t-MA.

In the majority of occupational settings within China, the concentrations of benzene are observed to fall markedly below the demarcated detection thresholds. Employing traditional risk assessment models, the presence of exceptionally low airborne benzene exposure concentrations may infuse heightened degrees of uncertainty. Consequently, the necessity arises to investigate risk assessment methodologies more apt for the prevalent exposure environment among employees. In the present study, a pharmacokinetic model premised on urinary benzene metabolites (S-PMA and t, t-MA) was employed to ascertain a more precise daily airborne benzene exposure concentration per individual. This value was integrated into the linear multistage model as the 'internal exposure concentration'. In conjunction with the U.S National Environmental Protection Agency's (EPA) inhalation risk assessment model predicated on the external exposure concentration, the Singapore Ministry of Manpower's (MOM) model, and the linear multistage (LMS) model, the carcinogenic and non-carcinogenic effects of benzene were evaluated for 1781 benzene-exposed employees across 76 enterprises in Jiangsu Province. Findings suggest that in the linear multilevel model assessment, the cancer risk levels based on t, t-MA and S-PMA were higher in the printing and recording media reproduction industry, automobile manufacturing industry, general equipment manufacturing industry and the furniture manufacturing industry (median 2.842 × 10-4, 2.819 × 10-4, 2.809 × 10-4, and 2.678 × 10-4), which align more consistently with the actual benzene exposure circumstances of each industry's study participants, with overall risk levels calculated by the linear multistage model exceeding those of the EPA inhalation risk assessment model and the MOM model. This implies that the linear multistage model of internal exposure, based on the reciprocal of benzene biomarkers S-PMA and t, t-MA for airborne benzene exposure, presents enhanced sensitivity and suitability for the current occupational health risk assessment of workers. Without doubt, biomarker-based benzene exposure risk assessment emerges as the optimal choice.

Remote Control of Energy Transformation-Based Cancer Imaging and Therapy.

Cancer treatment requires precise tumor-specific targeting at specific sites that allows for high-resolution diagnostic imaging and long-term patient-tailorable cancer therapy; while, minimizing side effects largely arising from non-targetability. This can be realized by harnessing exogenous remote stimuli, such as tissue-penetrative ultrasound, magnetic field, light, and radiation, that enable local activation for cancer imaging and therapy in deep tumors. A myriad of nanomedicines can be efficiently activated when the energy of such remote stimuli can be transformed into another type of energy. This review discusses the remote control of energy transformation for targetable, efficient, and long-term cancer imaging and therapy. Such ultrasonic, magnetic, photonic, radiative, and radioactive energy can be transformed into mechanical, thermal, chemical, and radiative energy to enable a variety of cancer imaging and treatment modalities. The current review article describes multimodal energy transformation where a serial cascade or multiple types of energy transformation occur. This review includes not only mechanical, chemical, hyperthermia, and radiation therapy but also emerging thermoelectric, pyroelectric, and piezoelectric therapies for cancer treatment. It also illustrates ultrasound, magnetic resonance, fluorescence, computed tomography, photoluminescence, and photoacoustic imaging-guided cancer therapies. It highlights afterglow imaging that can eliminate autofluorescence for sustained signal emission after the excitation.

Endoplasmic reticulum stress-related protein GRP78 and CHOP levels in synovial fluid correlate with disease progression of primary knee osteoarthritis: A cross-sectional study.

BACKGROUND: Endoplasmic reticulum (ER) stress has been shown to play an important role in osteoarthritis (OA). OBJECTIVE: This study was aimed at assessing the relationship of endoplasmic reticulum (ER) stress-related glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) concentrations in the serum/synovial fluid (SF) with disease severity of primary knee osteoarthritis (pkOA). METHODS: Patients with pkOA together with healthy individuals were consecutively recruited from our hospital. The levels of GRP78 and CHOP in serum / SF were detected using enzyme-linked immunosorbent assay. The levels of IL-6 and MMP-3 were also examined. Radiographic progression of pkOA was evaluated based on Kellgren-Lawrence (K-L) grades. Receiver Operating Characteristic (ROC) curves were used to assess the diagnostic value of GRP78/CHOP levels with regard to K-L grades. The assessment of clinical severity was conducted using the visual analogue scale (VAS), Oxford knee score (OKS), and Lequesne algofunctional index (LAI). RESULTS: A total of 140 pkOA patients and 140 healthy individuals were included. Serum GRP78 and CHOP levels in pkOA patients were not significantly different from those in healthy individuals. The SF GRP78 and CHOP levels in healthy controls were not detected due to ethical reasons. Compared to those with K-L grade 2 and 3, the pkOA patients with K-L grade 4 had higher GRP78 and CHOP levels in the SF with statistical significance. In addition, the pkOA patients with K-L grade 3 exhibited drastically upregulated GRP78 and CHOP concentrations in the SF compared to those with K-L grade 2. Positive correlations of GRP78 and CHOP levels with K-L grades, IL-6, and MMP-3 levels in the SF were observed. ROC curve analysis indicated that both GRP78 and CHOP levels may act as decent indicators with regard to OA. GRP78 and CHOP concentrations in the SF were positively correlated with VAS/LAI score and negatively associated with OKS score. CONCLUSION: The study indicated that GRP78 and CHOP levels in the SF but not the serum were positively correlated with disease severity of pkOA.

Enhancing the properties of soy protein isolate and dialdehyde starch films for food packaging applications through tannic acid crosslinking.

The utilization of naturally derived biodegradable polymers, including proteins, polysaccharides, and polyphenols, holds significant promise in addressing environmental concerns and reducing reliance on nonrenewable resources. This study aimed to develop films with enhanced UV resistance and antibacterial capabilities by covalently cross-linking soy protein isolate (SPI) with dialdehyde starch (DAS) through the incorporation of tannic acid (TA). The covalent crosslinking of TA with DAS and SPI was shown to establish a stable chemical cross-linking network. The tensile strength of the resulting SPI/DAS/15TA film exhibited a remarkable increase of 208.27 % compared to SPI alone and 52.99 % compared to SPI/DAS film. Notably, the UV absorption range of SPI/DAS/10TA films extended from 200 nm to 389 nm. This augmentation can be attributed to the oxidation of TA's phenolic hydroxyl groups to quinone under alkaline conditions, which then facilitated cross-linking with the SPI chain via Michael addition and Schiff base reactions. Furthermore, the film demonstrated robust antibacterial properties due to the incorporation of TA. Collectively, the observed properties highlight the significant potential of the SPI/DAS/10TA film for applications in food packaging, where its enhanced mechanical strength, UV resistance, and antibacterial characteristics can contribute to improved product preservation and safety.

Global trade-driven transfer of atmospheric polycyclic aromatic hydrocarbon emissions and associated human inhalation exposure risk.

Polycyclic aromatic hydrocarbons (PAHs) are of significant public concern because of their toxicity and long-range transport potential. Extensive studies have been conducted to explore the source-receptor relationships of PAHs via atmospheric transport. However, the transfer of trade-driven regional and global PAHs is poorly understood. This study estimated the virtual PAHs emission transfer embodied in global trade from 2004 to 2014 and simulated the impact of international trade on global contamination and associated human inhalation exposure risk of PAHs. Results show that trade-driven PAHs flowed primarily from developed to less-developed regions, particularly in those regions with intensive heavy industries and transportation. As the result, international trade resulted in an increasing risk of lung cancer induced by exposure to PAHs (27.8% in China, 14.7% in India, and 11.3% in Southeast Asia). In contrast, we found decreasing risks of PAHs-induced lung cancer in Western Europe (63.2%) and the United States (45.9%) in 2004. Our findings indicate that final demand and emission intensity are the key driving factors contributing to rising and falling consumption-based PAHs emissions and related health risk respectively. The results could provide a useful reference for global collaboration in the reduction of PAHs pollution and related health risks.