GSE1 promotes the proliferation and migration of lung adenocarcinoma cells by downregulating KLF6 expression.

Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF-HDAC complex (BHC) components in cells. The transcriptome of GSE1-knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p-value < .05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel-like factor 6). Indeed, quantitative reverse-transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non-small cell lung cancer cells through the downregulation of KLF6 expression.

Learning the Relation Between Similarity Loss and Clustering Loss in Self-Supervised Learning.

Self-supervised learning enables networks to learn discriminative features from massive data itself. Most state-of-the-art methods maximize the similarity between two augmentations of one image based on contrastive learning. By utilizing the consistency of two augmentations, the burden of manual annotations can be freed. Contrastive learning exploits instance-level information to learn robust features. However, the learned information is probably confined to different views of the same instance. In this paper, we attempt to leverage the similarity between two distinct images to boost representation in self-supervised learning. In contrast to instance-level information, the similarity between two distinct images may provide more useful information. Besides, we analyze the relation between similarity loss and feature-level cross-entropy loss. These two losses are essential for most deep learning methods. However, the relation between these two losses is not clear. Similarity loss helps obtain instance-level representation, while feature-level cross-entropy loss helps mine the similarity between two distinct images. We provide theoretical analyses and experiments to show that a suitable combination of these two losses can get state-of-the-art results. Code is available at https://github.com/guijiejie/ICCL.

Human Placental Extract Delays In Vitro Cellular Senescence through the Activation of NRF2-Mediated Antioxidant Pathway.

Senescent cells accumulate in the organs of aged animals and exacerbate organ dysfunction, resulting in age-related diseases. Oxidative stress accelerates cellular senescence. Placental extract, used in the alleviation of menopausal symptoms and promotion of wound healing and liver regeneration, reportedly protects against oxidative stress. In this study, we investigated the effects of human placental extract (HPE) on cellular senescence in normal human dermal fibroblasts (NHDFs) under oxidative stress conditions. We demonstrated that HPE delays the onset of cellular senescence. Next-generation sequencing analysis revealed that under oxidative stress conditions, HPE treatment enhanced the expression of the antioxidant genes CYGB, APOE, NQO1, and PTGS1. Further, HPE treatment under oxidative stress conditions increased the protein level of nuclear factor-erythroid factor 2-related factor 2 (NRF2)-a vital molecule in the antioxidant pathway-via post-transcriptional and/or post-translational regulations. These findings indicate that HPE treatment in NHDFs, under chronic oxidative stress, delays cellular senescence by mitigating oxidative stress via upregulation of the NRF2-mediated antioxidant pathway, and HPE treatment could potentially ameliorate skin-aging-associated damage, in vivo.

Preclinical evidence of the effect of quercetin on diabetic nephropathy: A meta-analysis of animal studies.

Quercetin, which is present in numerous fruits and vegetables, has shown promise in improving inflammation, lipid profiles, and blood pressure in humans. However, the efficacy of quercetin in diabetic nephropathy (DN) remains preclinical and unclear. Therefore, a meta-analysis based on preclinical animal data is needed to assess the efficacy, optimal dosage, and underlying mechanism of DN treatment to accelerate new drug research and clinical translation. We conducted a literature search in PubMed, Embase, Web of Science, and Cochrane Library to retrieve randomized controlled trials evaluating the effects of quercetin in rat or mouse diabetic models. We assessed the quality of the studies individually according to SYRCLE's risk of bias tool for animal studies. Twenty animal studies, including 378 animals, were included in the meta-analysis. Meta-analysis data showed that renal function indices, such as renal index, urine protein, uric acid, urine albumin, and serum creatinine levels, significantly improved with quercetin administration. However, no significant association was observed between quercetin and creatinine clearance. Quercetin remarkably alleviated oxidative stress by reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) and catalase (CAT) activities. In addition, quercetin exhibits anti-inflammatory activity by reducing tumor necrosis factor-α（TNF-α）and interleukin-1ß（IL-1ß）levels. Subgroup analysis performed using quercetin doses and animal species indicated that animal species were a source of heterogeneity. This meta-analysis suggests that quercetin is a promising drug for DN treatment, facilitating clinical prediction and therapy.

Mechanosensitive axon outgrowth mediated by L1-laminin clutch interface.

Mechanical properties of the extracellular environment modulate axon outgrowth. Growth cones at the tip of extending axons generate traction force for axon outgrowth by transmitting the force of actin filament retrograde flow, produced by actomyosin contraction and F-actin polymerization, to adhesive substrates through clutch and cell adhesion molecules. A molecular clutch between the actin filament flow and substrate is proposed to contribute to cellular mechanosensing. However, the molecular identity of the clutch interface responsible for mechanosensitive growth cone advance is unknown. We previously reported that mechanical coupling between actin filament retrograde flow and adhesive substrates through the clutch molecule shootin1a and the cell adhesion molecule L1 generates traction force for axon outgrowth and guidance. Here, we show that cultured mouse hippocampal neurons extend longer axons on stiffer substrates under elastic conditions that correspond to the soft brain environments. We demonstrate that this stiffness-dependent axon outgrowth requires actin-adhesion coupling mediated by shootin1a, L1, and laminin on the substrate. Speckle imaging analyses showed that L1 at the growth cone membrane switches between two adhesive states: L1 that is immobilized and that undergoes retrograde movement on the substrate. The duration of the immobilized phase was longer on stiffer substrates; this was accompanied by increases in actin-adhesion coupling and in the traction force exerted on the substrate. These data suggest that the interaction between L1 and laminin is enhanced on stiffer substrates, thereby promoting force generation for axon outgrowth.

Overexpression of GSE1 Related to Trastuzumab Resistance in Gastric Cancer Cells.

Gastric cancer is one of the most prevalent human cancers with poor prognosis. Trastuzumab is a well-used targeted drug for gastric cancer with HER2 amplification. Trastuzumab resistance restrains the clinical use of trastuzumab. In this study, we reported human Gse1 coiled-coil protein (GSE1) promoted trastuzumab resistance in HER2-positive gastric cancer cells. Acquired trastuzumab-resistant gastric cancer cells overexpressed GSE1, and depletion of GSE1 decreased the trastuzumab resistance of trastuzumab-resistant gastric cancer cells. BCL-2 was a downstream gene positively regulated by GSE1 and also performed promoting the role of trastuzumab resistance in HER2-positive gastric cancer cells. A high level of GSE1 was associated with a high risk of tumor lymph node metastasis and higher clinical stage in HER2-positive gastric cancer patients. GSE1 was a potential target that could be used for HER2-positive gastric cancer therapy.

Shootins mediate collective cell migration and organogenesis of the zebrafish posterior lateral line system.

The zebrafish sensory posterior lateral line is an excellent model system to study collective cell migration and organogenesis. Shootin1 is a cytoplasmic protein involved in neuronal polarization and axon guidance. Previous studies have shown that shootin1 couples actin filament retrograde flow with extracellular adhesive substrates at the leading edge of axonal growth cones, thereby producing mechanical force for the migration and guidance of axonal growth cones. However, the functions of shootin in peripheral cells remain unknown. Here we identified two novel shootin family members, shootin2 and shootin3. In zebrafish, shootin1 and shootin3 are expressed in the posterior lateral line primordium (PLLP) and neuromasts during embryonic development. A shootin1 mutant displayed a reduced speed of PLLP migration, while shootin1;shootin3 double mutation inhibited cell proliferation in the PLLP. Furthermore, our results suggest that shootin1 and shootin3 positively regulate the number of neuromasts and the number of cells in deposited neuromasts. Our study demonstrates that shootins mediate collective cell migration of the posterior lateral line primordium and formation of neuromasts in zebrafish.

Rab33a and Rab33ba mediate the outgrowth of forebrain commissural axons in the zebrafish brain.

Rab small GTPases play key roles in intracellular membrane trafficking. Rab33a promotes axon outgrowth of cultured rat hippocampal neurons by mediating the anterograde axonal transport of Golgi-derived vesicles and the concomitant exocytosis of these vesicles at the growth cone. However, the functions of Rab33 in vivo are unclear. Here, we show that zebrafish rab33a and rab33ba are orthologs of mammalian Rab33a and Rab33b, respectively. They are expressed in the developing brain, including in neurons of the telencephalic dorsorostral cluster and the diencephalic ventrorostral cluster, which project axons to form the anterior and postoptic commissures, respectively. Although rab33a single mutant and rab33ba single mutant fish did not show remarkable defects, fish carrying the rab33a;rab33ba double mutations displayed dysgenesis of the anterior and postoptic commissures. Single-cell labeling in the telencephalic dorsorostral cluster demonstrated that the rab33a;rab33ba double mutation inhibits axonal extension in the anterior commissure. These results suggest that Rab33a and Rab33ba mediate axon outgrowth and the formation of the forebrain commissures in the zebrafish brain in a cooperative manner.

Some Wilker and Cusa type inequalities for generalized trigonometric and hyperbolic functions.

The authors obtain some Wilker and Cusa type inequalities for generalized trigonometric and hyperbolic functions and generalize some known inequalities.

Some monotonicity properties and inequalities for the generalized digamma and polygamma functions.

Several monotonicity and concavity results related to the generalized digamma and polygamma functions are presented. This extends and generalizes the main results of Qi and Guo and others.

An inequality for generalized complete elliptic integral.

In this paper, we show an elegant inequality involving the ratio of generalized complete elliptic integrals of the first kind and generalize an interesting result of Alzer.