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Protein ubiquitination is an important mechanism for regulating the activity and levels of proteins under physiological conditions. Loss of regulation by protein ubiquitination leads to various diseases, such as cancer. Two types of enzymes, namely, E1/E2/E3 ligases and deubiquitinases, are responsible for controlling protein ubiquitination. The ubiquitin-specific peptidases (USPs) are the main members of the deubiquitinase family. Many studies have addressed the roles of USPs in various diseases. An increasing number of studies have indicated that USPs are critical for cancer progression, and some USPs have been used as targets to develop inhibitors for cancer prevention. Herein we collect and organize most of the recent studies on the roles of USPs in cancer progression and discuss the development of USP inhibitors for cancer therapy in the future.

Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of EGF‐induced COX‐2 and angiopoietin‐like 4 (ANGPTL4) on HNSCC metastasis remains unclear. In this study, we revealed that the expression of ANGPTL4 is essential for COX‐2‐derived prostaglandin E2 (PGE2)‐induced tumor cell metastasis. We showed that EGF‐induced ANGPTL4 expression was dramatically inhibited with the depletion and inactivation of COX‐2 by knockdown of COX‐2 and celecoxib treatment, respectively. Prostaglandin E2 induced ANGPTL4 expression in a time‐ and dose‐dependent manners in various HNSCC cell lines through the ERK pathway. In addition, the depletion of ANGPTL4 and MMP1 significantly impeded the PGE2‐induced transendothelial invasion ability of HNSCC cells and the binding of tumor cells to endothelial cells. The induction of molecules involved in the regulation of epithelial‐mesenchymal transition was also dependent on ANGPTL4 expression in PGE2‐treated cells. The depletion of ANGPTL4 further blocked PGE2‐primed tumor cell metastatic seeding of lungs. These results indicate that the EGF‐activated PGE2/ANGPTL4 axis enhanced HNSCC metastasis. The concurrent expression of COX‐2 and ANGPTL4 in HNSCC tumor specimens provides insight into potential therapeutic targets for the treatment of EGFR‐associated HNSCC metastasis. Metastasis is the major cause of cancer mortality. However, there is no significant improvement in treating advanced head and neck cancer. Our finding indicates that the monitoring levels of angiopoietin‐like 4 (ANGPTL4) are necessary for the treatment of inflammation‐ and/or growth factor‐mediated advanced or metastatic head and neck cancer. The expression of ANGPTL4, a potent angiogenetic factor in cancer, is essential for head and neck cancer metastasis caused by inflammatory response and growth factor stimulation. Therefore, the use of antiinflammatory medicines such as nonsteroidal antiinflammatory drugs and targeting ANGPTL4 could be considered as alternative approaches in treating and preventing the recurrence of head and neck cancer.

Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. Results Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. Conclusion Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine––CCL5 displays neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.In addition to neuroinflammatory functions, chemokine CCL5 shows strong neurotrophic properties. In this study, we found that CCL5 facilitates hippocampal glucoregulatory efficiency. CCL5 promotes aerobic glucose metabolism, mitochondrial ATP generation and purine synthesis, improving synaptic plasticity and enhancing memory and cognition functions.

PurposeDue to the internationalization that has occurred during the past few decades, the living conditions of people around the island of Taiwan have gradually changed, especially their eating habits. Among them, the growth of the coffee market has been very significant. To date, many studies have been devoted to exploring the application of experiential marketing (EM) in a variety of industries. Many experimental results have proven that a positive brand image (BI) will lead to brand loyalty (BL). In services, the best at the practice of EM is Starbucks. Therefore, this paper aims to assess the role of BI in EM and BL for Taiwan’s most popular brand, Starbucks.Design/methodology/approachIn the formal test stage, 225 questionnaires were given to respondents in Starbucks located in four districts (Da-An, Zhong-Zheng, Nei-Hu and Xi-Yin), which have many more stores than the other districts in Taipei City. Two hundred valid samples were obtained. This study used structural equation modelling (SEM) to validate the relationships among EM, BI and BL.FindingsThe findings show that EM cannot directly impact BL as expected, as it needs BI to do so. In other words, BI acts a complete mediator in the relationship between EM and BL.Practical implicationsIn this study, BI acts a complete mediator. This means that if Starbucks expects to improve consumers’ loyalty to the brand, it only needs to rely on the good overall image of the brand. Facing such business style homogeneity, people need some available information to help them to execute their following purchase decisions. Though Starbucks can bring me to its locations, meaning that Starbucks has made its first move in comparison with other competitors, I still decide to leave without any impressive image of this brand. Accordingly, we can refer to BI as a powerful endorsement of a qualified relationship between EM and BL.Originality/valueCompared to past studies on Taiwan’s/Taipei’s Starbucks, this paper simultaneously inputs EM, BI and BL into the model. Though Starbucks has achieved great EM success, this study finds that EM is no longer exclusive to BL, and BI is a powerful endorsement of a qualified relationship between EM and BL. For Starbucks, it must strengthen consumer perceptions of its BI to create customer loyalty.

Generation Z, who are prospective customers, are digital natives. As the infrastructure and technology of the internet have developed, this study examines whether digital disruption demonstrates the uniqueness of Generation Z and affects their attitudes toward products they rarely see. Digital media, social network sites, and instant messaging are emphasized due to their relationship to digital disruption. Social networks (e.g., social network sites and instant messaging) encourage interactions and are therefore separate from digital media. The questionnaire in this study was based on a thorough literature review, and reliability and validity were ensured. A total of 505 responses were used for hypothesis testing by the bootstrapping method and ordinary least squares. The results partially comply with the suggestion that Generation Z depends more on information from digital media than previous generations. However, social networks have a greater effect than digital media and do not show generational differences. Although the nature and lifestyle differ across generations, certain circumstances (e.g., working requirements) cause people to not conform to the stereotype of a specific generation. Hence, digital disruption creates generational differences, but these differences can be eliminated through practice. Given the development of digital innovation and its wider systemic effects, this study discusses the disruption of digital technology and the emergence of digital natives. The influences and the interactions identified establish a foundation for empirical practitioners and future researchers.

This study aimed to evaluate the antiglycation effects of adlay on protein glycation using in vitro glycation assays. Adlay seed was divided into the following four parts: the hull (AH), testa (AT), bran (AB), and polished adlay (PA). A solvent extraction technique and column chromatography were utilized to investigate the active fractions and components of adlay. Based on a BSA-glucose assay, the ethanolic extracts of AT (ATE) and AB (ABE) revealed a greater capacity to inhibit protein glycation. ATE was further consecutively partitioned into four solvent fractions with n-hexane, ethyl acetate (ATE-Ea), 1-butanol (ATE-BuOH), and water. ATE-BuOH and -Ea show marked inhibition of glucose-mediated glycation. Medium–high polarity subfractions eluted from ATE-BuOH below 50% methanol with Diaion HP-20, ATE-BuOH-c to -f, exhibited superior antiglycation activity, with a maximum inhibitory percentage of 88%. Two phenolic compounds, chlorogenic acid and ferulic acid, identified in ATE-BuOH with HPLC, exhibited potent inhibition of the individual stage of protein glycation and its subsequent crosslinking, as evaluated by the BSA-glucose assay, BS-methylglyoxal (MGO) assay, and G.K. peptide-ribose assay. In conclusion, this study demonstrated the antiglycation properties of ATE in vitro that suggest a beneficial effect in targeting hyperglycemia-mediated protein modification.

2D van der Waals ferroelectrics have emerged as an attractive building block with immense potential to provide multifunctionality in nanoelectronics. Although several accomplishments have been reported in ferroelectric switching for out-of-plane ferroelectrics down to the monolayer, a purely in-plane ferroelectric has not been experimentally validated at the monolayer thickness. Herein, an in-plane ferroelectricity is demonstrated for micrometer-size monolayer SnS at room temperature. SnS has been commonly regarded to exhibit the odd–even effect, where the centrosymmetry breaks only in the odd-number layers to exhibit ferroelectricity. Remarkably, however, a robust room temperature ferroelectricity exists in SnS below a critical thickness of 15 layers with both an odd and even number of layers, suggesting the possibility of controlling the stacking sequence of multilayer SnS beyond the limit of ferroelectricity in the monolayer. This work will pave the way for nanoscale ferroelectric applications based on SnS as a platform for in-plane ferroelectrics. Out-of-plane ferroelectricity is usually unstable in the two dimensional limit due to the presence of the depolarization field. Here, the authors successfully circumvent this issue by growing µm-sized SnS monolayers that exhibit in-plane ferroelectricity that is stable at room temperature.

Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient.