Hypoxia-induced exosomes promote hepatocellular carcinoma proliferation and metastasis via miR-1273f transfer.

Exosomes are present within the local hypoxic tumor microenvironment, where they are able to transfer microRNAs between cells, thereby, effectively mediating cell-cell communication. Hypoxia plays a pivotal role in the progression of many tumor types such as hepatocellular carcinoma (HCC), but how hypoxia-induced exosomes in HCC affect HCC cells remains uncertain. In the present study, we found that hypoxic conditions induced increased exosomal production by HCC cells, and these exosomes, in turn, enhanced the proliferation, migration, and invasiveness in addition to epithelial-to-mesenchymal transition (EMT) in HCC cells under normoxic conditions. When we analyzed these exosomes, we found that miR-1273f were present at higher levels under hypoxic conditions, and we determined that this miRNA was responsible for directly replicating the effects of hypoxic exosomes within HCC cells, in addition to activating the Wnt/ß-catenin signaling. We finally identified LHX6, which is a known inhibitor of the Wnt/ß-catenin pathway, to be a miR-1273f target. These results, thus, provide evidence that hypoxic conditions can lead HCC cells to express increased exosomes that facilitate miR-1273f expression in normoxic cells, thereby enhancing their malignant phenotype at least in part by targeting LHX6 for downregulation.

TCM syndrome differentiation in colorectal cancer patients assisted by differences in gut microbiota: An exploratory study.

Objective: To explore the difference in gut microbiota between different traditional Chinese Medicine (TCM) syndromes in patients with colorectal cancer (CRC) and its internal relationship. Methods: From June 2020 to August 2021, 109 colorectal cancer patients with a clear pathological diagnosis who had not yet undergone surgery or chemotherapy were classified according to the TCM syndrome classification, and the feces samples of 109 patients with preoperative colorectal cancer were collected. 16s rRNA gene sequencing was used to determine gut microbiota diversity and abundance in CRC patients with different TCM syndrome, and LEfSe analysis was made to screen different TCM syndrome for differential representative microbiota. Results: 109 patients were divided into 5 syndromes by TCM syndrome classification, which were Liver and Kidney Yin Deficiency Syndrome (LKYDS, n = 19), Spleen Deficient Qi Stagnation Syndrome (SDQSS, n = 30), Stasis and Poison Obstruction Syndrome (SPOS, n = 17), Damp-Heat Syndrome (DHS, n = 30), Qi and Blood Deficiency Syndrome (QBDS, n = 13). Alpha diversity index showed significant differences among the five groups of TCM syndromes, with Shannon index being highest in the SDQSS group and lowest in the LKYDS (p = 0.003). ACE index being highest in the SDQSS group and lowest in the SPOS (p = 0.010). PD whole tree index being highest in the SDQSS group and lowest in the SPOS (p = 0.017). Similarly, beta diversity showed significant differences among the five groups of TCM syndromes, with principal coordinate analysis (PCo1 = 31.86 %, PCo2 = 5.62 %) showing separation and coincidence between the groups, and Adonis group differences showing coincidence between the QBDS-LKYDS (p = 0.702), QBDS-DHS (p = 0.133), and SDQSS-DHS (p = 0.260) groups. LEfSe analysis revealed that the representative microbiota of DHS patients was Dialister sp Marseille P5638 (LDA = 3.05, p＜0.001), the representative microbiota of SPOS patients was Oscillospirales (LDA = 4.78, p = 0.029), the representative microbiota of SDQSS patients was Selenomonadaceae (LDA = 3.94, p = 0.003), the representative microbiota of LKYDS patients was Dialister (LDA = 4.19, p = 0.001), and the representative microbiota of QBDS patients was Akkermansia muciniphila (LDA = 4.23, p = 0.006). Conclusions: There are significant differences in gut microbiota between different TCM syndromes in CRC patients. The five microbiota, Dialister sp Marseille P5638, Oscillospirales, Selenomonadaceae, Dialister, and Akkermansia muciniphila, may be differential markers of TCM syndrome in CRC and are expected to be one of the bases for accurate TCM syndrome differentiation of CRC.

Erratum: Mir-484 contributes to diminished ovarian reserve by regulating granulosa cell function via YAP1-mediated mitochondrial function and apoptosis: Erratum.

[This corrects the article DOI: 10.7150/ijbs.68028.].

Bisphenol A and its analogue bisphenol S exposure reduce estradiol synthesis via the ROS-mediated PERK/ATF4 signaling pathway.

As a kind of endocrine-disrupting chemicals, BPA may affect the human placenta. Due to consumer unease about BPA, many manufacturers are using alternatives to BPA, such as BPS. However, some reports suggest that BPS may produce similar results to BPA. To understand how BPA/BPS leads to reduced synthesis of placental estradiol (E2), we conducted studies using a human choriocarcinoma cell (JEG-3) model for research. In this study. Elisa assay revealed that both BPA/BPS exposures decreased E2 synthesis in JEG-3 cells. The results of RT-PCR showed that both BPA and BPS could reduce the mRNA expression of CYP19A1, a key enzyme for E2 synthesis in JEG-3 cells. In addition, Western blot assay showed that BPA/BPS-induced ER-stress PERK/eIF2α/ATF4 signaling protein expression was increased. The expression of ROS in cells after exposure to BPA/BPS was detected using the 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) method. The results of this experiment showed that BPA/BPS significantly induced an inhibition of ROS in JEG-3 cells. The present study concluded that, firstly, BPS exposure induced almost the same effect as BPA in reducing E2 synthesis in JEG-3 cells. Second, BPA/BPS exposure may reduce E2 synthesis in JEG-3 cells by increasing ROS levels and thus activating endoplasmic reticulum stress.

Mir-484 contributes to diminished ovarian reserve by regulating granulosa cell function via YAP1-mediated mitochondrial function and apoptosis.

Women with diminished ovarian reserve (DOR) have reduced fertility, but the underlying regulation of ovarian function remains unknown. Although differential microRNA (miRNA) expression has been described in several ovarian disorders, little is known about the role of miRNAs in the pathogenesis of DOR. In this study, we investigated the expression levels of miR-484 in granulosa cells (GCs) derived from human follicular fluid, and explored their correlation with female ovarian reserve function as well as clinical outcomes of assisted reproduction technology (ART). Additionally, we investigated the effects of miR-484 on the biological functions of GC cell lines in vitro. We found that miR-484 was highly expressed in GCs from DOR patients and was correlated with decreasing AMH levels and AFC, as well as increasing FSH levels, but not with LH, progesterone, or estradiol. Additionally, miR-484 was negatively related to the number of retrieved oocytes and the ratio of high-quality embryos. Moreover, we found that miR-484 repressed the proliferation of GCs and induced apoptosis, which can in part be attributed to mitochondrial dysfunction. Conversely, silencing miR-484 had the opposite effect. Multiple approaches, including bioinformatic analysis, RNA-seq, qPCR, immunofluorescence, western blotting and luciferase reporter assays, identified YAP1 as a direct target of miR-484 in GCs. Additionally, reintroduction of YAP1 rescued the effects of miR-484 in GCs. The present study indicates that miR-484 can directly target the mRNA of YAP1, induce mitochondrial dysfunction, and consequently reduce the viability and promote the apoptosis of granulosa cells, which contributes to the pathogenesis of DOR.

Magnetic and magnetothermal properties, and the magnetic phase diagram of single-crystal holmium along the easy magnetization direction.

The magnetic and magnetothermal properties of holmium single crystal have been investigated from 4.2 to 300 K in magnetic fields up to 100 kOe using magnetization and heat capacity data measured along the easy magnetization direction, which is the crystallographic b-axis, i.e. [112¯0] direction. The magnetic phase diagram of Ho has been refined by examining data measured using a high purity single crystal.