Circ_0050444 represses esophageal squamous cell carcinoma progression through sponging miR-486-3p to upregulate C10orf91.

Esophageal squamous cell carcinoma (ESCC) ranks as the fourth leading cause of tumor-related deaths in China. Circ_0050444 has been revealed to be downregulated in ESCC tissues, however, its function and molecular mechanism underlying ESCC progression is unknown. Therefore, we attempted to clarify the functional role and molecular mechanism of circ_0050444 underlying ESCC progression. RT-qPCR and RNase R digestion assays were used to evaluate circ_0050444 expression and stability characteristics in ESCC cells. Gain-of-function assays were conducted to clarify circ_0050444 role in ESCC cell malignant behaviors. Bioinformatics and mechanism experiments were performed to assess the relationship between circ_0050444 or C10orf91 and miR-486-3p in ESCC cells. Rescue assays were conducted to evaluate the regulatory function of the circ_0050444-miR-486-3p-C10orf91 axis in ESCC cellular processes. Circ_0050444 expression was found to be downregulated both in ESCC patient tissues and cell lines. Functionally, circ_0050444 overexpression repressed ESCC cell proliferative, migratory, and invasive capabilities in cultured cells. Mechanistically, circ_0050444 was found to be competitively bound with miR-486-3p to upregulate C10orf91 in ESCC cells. Moreover, the impact of circ_0050444 elevation on ESCC cell proliferation, migration, and invasion was countervailed by C10orf91 silencing. Circ_0050444 presents downregulation and functions as a tumor suppressor in ESCC progression. Circ_0050444 suppresses ESCC proliferation, migration, and invasion through sponging miR-486-3p to upregulate C10orf91, providing a potential new direction for seeking therapeutic plans for ESCC.

Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis.

Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth, differentiation, and survival. The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease. Thus, the identification of SHP2 activators and a complete understanding of their mechanism is required. We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation. Oleanolic acid was identified as a suitable candidate. By binding to R362, K364, and K366 in the active center of the PTP domain, oleanolic acid maintained the active open state of SHP2, which facilitated the binding between SHP2 and its substrate. This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rα and inhibiting the activation of STAT3. Furthermore, via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis, oleanolic acid effectively mitigated colitis in mice. This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099. These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity.

Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.

Salvianolic acid A prevents UV-induced skin damage by inhibiting the cGAS-STING pathway.

DNA damage resulting from UV irradiation on the skin has been extensively documented in numerous studies. In our prior investigations, we demonstrated that UVB-induced DNA breakage from keratinocytes can activate the cGAS-STING pathway in macrophages. The cGAS-STING signaling pathway serves as the principal effector for detecting and responding to abnormal double-stranded DNA in the cytoplasm. Expanding on our previous findings, we have further validated that STING knockout significantly diminishes UVB-induced skin damage, emphasizing the critical role of cGAS-STING activation in this context. Salvianolic acid A, a principal active constituent of Salvia miltiorrhiza Burge, has been extensively studied for its therapeutic effects in conditions such as coronary heart disease, angina pectoris, and diabetic peripheral neuropathy. However, its effect on cGAS-STING pathway and its ability to alleviate skin damage have not been previously reported. In a co-culture system, supernatant from UVB-treated keratinocytes induced IRF3 activation in macrophages, and this activation was inhibited by salvianolic acid A. Our investigation, employing photodamage and photoaging models, establishes that salvianolic acid A effectively mitigates UV-induced epidermal thickening and collagen degeneration. Treatment with salvianolic acid A significantly reduced skin damage, epidermal thickness increase, and keratinocyte hyperproliferation compared to the untreated photo-damage and photoaging model groups. In summary, salvianolic acid A emerges as a promising candidate for preventing UV-induced skin damage by inhibiting cGAS-STING activation. This research enhances our understanding of the intricate mechanisms underlying skin photodamage and provides a potential avenue for the development of therapeutic interventions.

Effects of Online Game and Short Video Behavior on Academic Delay of Gratification - Mediating Effects of Anxiety, Depression and Retrospective Memory.

Objective: Learner dependence on short videos has many pitfalls for learning outcomes, but the negative effects of excessive short video use have been little discussed in the learning psychology literature. Therefore, this study investigated the effects of excessive short video use on anxiety, depression, prospective memory, and academically delayed gratification (ADOG) in relation to online gaming-related behaviours, and explored the possible mechanisms by which excessive online gaming and short video use may lead to decreased ADOG, to expand our understanding of excessive short video use. Methods: Based on the whole class random sampling method, a questionnaire survey was conducted among college students in Northern Anhui, China from May 7 to July 27, 2022. The questionnaires included the Generalized Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire Scale (PHQ-9), Prospective and Retrospective Memory (PRM) Questionnaire, and ADOG Scale. Results: A total of 1016 participants completed the survey. The study found that of all the internet behaviors, 20.8% of the college students mainly played online games, 43.9% mainly played short videos, and 35.3% conducted other online behaviors. When compared with other internet behaviors, online gaming and short video behaviors can cause more serious anxiety/depression and worse PRM and ADOG scores. As time spent playing online games and short videos increased, anxiety and depression became worse, and the scores for PRM and ADOG also declined. Anxiety, depression, and PRM mediate the relationship between time spent on online gaming/short videos and ADOG. Conclusion: Excessive short videos behaviour may produce the same psychological problems and learning problems as online gaming disorder. Excessive short video and online gaming behaviors may affect ADOG performance through anxiety, depression, and prospective memory. These findings could be used as a basis for future studies on the improvement of ADOG.

Targeting 14-3-3ζ by a small-molecule compound AI-34 maintains epithelial barrier integrity and alleviates colitis in mice via stabilizing ß-catenin.

Aberrant intestinal epithelial barrier function is the primary pathology of Ulcerative colitis (UC), making it a desirable drug target. In this study, our small-molecule compound AI-34 exerted a significant protective effect in an LPS-induced epithelial barrier injury model. In vitro, AI-34 treatment significantly decreased cell permeability, increased transmembrane resistance, and maintained the junctional protein (ZO-1 and E-cadherin) levels in monolayer cells. Using the LiP-small molecule mapping approach (LiP-SMap), we demonstrated that AI-34 binds to 14-3-3ζ. AI-34 promoted the interaction between 14-3-3ζ and ß-catenin, decreasing the ubiquitination of ß-catenin and thus maintaining intestinal epithelial barrier function. Finally, AI-34 triggered the stabilization of ß-catenin mediated by 14-3-3ζ, provoking a significant improvement in the DSS-induced colitis model. Our findings suggest that AI-34 may be a promising candidate for UC treatment.

The chain-mediation pathway of gender regarding academic delay of gratification in college students is regulated by anxiety/depressive mood and prospective memory.

Objective: This study investigated the relationship between gender and academic delay of gratification (ADOG) in college students and explored the mediating roles of anxiety/depressive mood and prospective memory to provide a theoretical intervention approach based on internal mechanisms. Methods: Random cluster sampling was conducted on 609 students from three universities situated in the Province of Anhui, China with the use of data from several questionnaires: the general information questionnaire, Generalized Anxiety Disorder Scale, Patient Health Questionnaire, Prospective and Retrospective Memory (PRM) Questionnaire, and ADOG Scale. Results: The females' anxiety and depression levels were lower than that of the males, while the female PRM and ADOG performance improved when compared to that of the males. Anxiety and depression were negatively correlated with PRM and ADOG, respectively, whereas the PRM and ADOG data demonstrated a positive correlation. Depression/anxiety and prospective memory also played a chain intermediary role between gender and ADOG. Conclusion: Gender not only directly affects college students' ADOG, but it also has indirect effects through depression/anxiety and prospective memory. Therefore, it is very important to treat students' mental health differently according to gender to improve prospective memory and delayed academic satisfaction.

Spirodalesol analog 8A inhibits NLRP3 inflammasome activation and attenuates inflammatory disease by directly targeting adaptor protein ASC.

Pharmacological inhibition of the Nod-like receptor family protein 3 (NLRP3) inflammasome contributes to the treatment of numerous inflammation-related diseases, making it a desirable drug target. Spirodalesol, derived from the ascomycete fungus Daldinia eschscholzii, has been reported to inhibit NLRP3 inflammasome activation. Based on the structure of spirodalesol, we synthesized and screened a series of analogs to find a more potent inhibitor. Analog compound 8A was identified as the most potent selective inhibitor for NLRP3 inflammasome assembly, but 8A did not inhibit the priming phase of the inflammasome. Specifically, while 8A did not reduce NLRP3 oligomerization, we found that it inhibited the oligomerization of adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), as ASC speck formation was significantly reduced. Also, 8A interrupted the assembly of the NLRP3 inflammasome complex and inhibited the activation of caspase-1. Subsequently, we used a cellular thermal shift assay and microscale thermophoresis assay to demonstrate that 8A interacts directly with ASC, both in vitro and ex vivo. Further, 8A alleviated lipopolysaccharide-induced endotoxemia, as well as monosodium urate-induced peritonitis and gouty arthritis in mice by suppressing NLRP3 inflammasome activation. Thus, 8A was identified as a promising ASC inhibitor to treat inflammasome-driven diseases.

Controllable Surface-Grafted MXene Inks for Electromagnetic Wave Modulation and Infrared Anti-Counterfeiting Applications.

Two-dimensional transition metal carbide/nitride (MXene) conductive inks are promising for scalable production of printable electronics, electromagnetic devices, and multifunctional coatings. However, the susceptible oxidation and poor rheological property seriously impede the printability of MXene inks and the exploration of functional devices. Here, we proposed a controllable surface grafting strategy for MXene flakes (p-MXene) with prepolymerized polydopamine macromolecules to protect against water and oxygen, enrich surface chemistry, and significantly optimize the rheological properties of the inks. The obtained p-MXene inks can adapt to screen-printing and other high-viscosity processing techniques, facilitating the development of patterned electromagnetic films and coatings. Interestingly, the printed MXene polarizer can freely switch and quantitatively control microwave transmission, giving an inspiring means for smart microwave modulation beyond the commonly reported shielding function. Moreover, the introduction of polydopamine nanoshell enables the infrared emissivity of MXene coating to be adjusted to a large extent, which can produce infrared anti-counterfeiting patterns in a thermal imager. Therefore, multifunctional antioxidant p-MXene inks will greatly extend the potential applications for the next-generation printable electronics and devices.

How Government Size Expansion Can Affect Green Innovation-An Empirical Analysis of Data on Cross-Country Green Patent Filings.

The expansion of government size will have dual effects on a country's green innovation. An appropriately sized government size increases marginal productivity and stimulates the development of green innovation by increasing government expenditure. On the contrary, an excessively sized government creates a huge administrative agency, which not only increases the tax burden but also damages social welfare by excessive intervention. Therefore, the effect of government size on green innovation is not linear. In order to prove this proposition, this study examines the impact of government size on green innovation in 166 countries between 1995 and 2018, using a two-way fixed effects model. The results reveal an inverted U-shaped relationship between government size and the level of green innovation, indicating that optimal government size may maximize a country's green innovation output. The results further suggest that this inverted U-shaped relationship is mainly influenced by environmental regulations and financial support. Finally, our heterogeneity analysis demonstrates that the inverted U-shaped relationship is more pronounced for countries with high organizational inertia and more R&D expenditure than for those with low organizational inertia and less R&D expenditure. This finding makes up for the research gap between government size and green innovation and provides a reference for countries to formulate the optimal government size to improve the level of green innovation.

Improvement of magnesium isoglycyrrhizinate on DSS-induced acute and chronic colitis.

Inflammatory bowel disease (IBD) is a worldwide prototypical complex disease, owing to its multifactorial causes, relapsing and remitting condition and high incidence. Thus, effective therapeutic approaches need to be developed for patients with IBD. Currently, we reported the improving effect of magnesium isoglycyrrhizinate on colitis induced by dextran sulfate sodium (DSS). We found that magnesium isoglycyrrhizinate treatment significantly alleviated DSS-induced acute and chronic colitis by inhibiting the inflammatory response characterized by reduce of the infiltrations of immune cell and the level of pro-inflammatory cytokines. Besides, magnesium isoglycyrrhizinate treatment significantly inhibited the level of ROS and decreased the gut barrier destruction after DSS treatment. Furthermore, the results also showed that administration of magnesium isoglycyrrhizinate significantly reduced the colonic fibrosis. Taken together, these results revealed the potency of magnesium isoglycyrrhizinate on the intestinal inflammation, by which points to the possible use of magnesium isoglycyrrhizinate for IBD therapy in clinical applications.

Andrographolide sulfonate ameliorates chronic colitis induced by TNBS in mice via decreasing inflammation and fibrosis.

Inflammatory bowel disease could result in diarrhea and abdominal pain, as well as potential complications such as tissue fibrosis. The therapeutic effect of andrographolide sulfonate on acute murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) has been confirmed. In the study here, chronic colitis triggered by repeated intrarectal administration of TNBS was established and the effect of andrographolide sulfonate was examined. Repeated TNBS administration induced substantial mice death, which was significantly decreased by andrographolide sulfonate treatment. The elevation of inflammatory cytokines including IL-6, IL-17A, TNF-α as well as IFN-γ in colonic tissues levels were decreased after administration of andrographolide sulfonate. Next, CD4+ T cell and macrophage infiltration was found to descend. The subset of pathogenic CD4+ T cell subset including CD4+IFN-γ+ (Th1) and CD4+IL-17A+ (Th17) were also suppressed by andrographolide sulfonate. Further, the restrain of p38 and p65 activation were also observed after andrographolide sulfonate administration. Finally, TNBS-induced colonic epithelial damage as well as fibrosis were significantly mitigated by andrographolide sulfonate. Based on the results got here, we can make a conclusion that andrographolide sulfonate could decrease inflammation and epithelial damage as well as fibrosis thus ameliorating chronic colitis in mice. Our study suggest the possible use of andrographolide sulfonate for chronic colitis treatment in clinical.

An Approach to Peri-Fused Heterocycles: A Metal-Mediated Cascade Carbonylative Cyclization/Dearomatic Diels-Alder Reaction.

A short and efficient route to peri-fused heterocycles has been developed. The transition metal in cooperation with the imino directing group cleaves the C-P bond of the phosphirane, followed by 1,1-insertion of CO and reductive elimination to give a reactive azaphosphacyclohexone derivative. The further dearomatic Diels-Alder reaction of the in situ-generated azaphosphacyclohexone with alkenes provides an array of annulated heterodecalins with high molecular complexity and atomic utilization.