ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

Hierarchical mesoporous TiO2/starch-based microparticles used as an efficient and reusable adsorbent for removal of water-soluble dye.

The widespread use of organic dyes in various industrial applications, driven by rapid industrialization, has become a significant environmental concern. Thus, highly efficient and reusable adsorbent for removal of pollutant dyes have gained increasing attention in water treatment. In this study, we present TiO2 nanoparticle-embedded mesoporous starch-based microparticle (TiO2@MSMP) with hierarchical rose-like structure were synthesis by using acetone precipitation of short-chain glucan (SCG) obtained from waxy maize starch. The resulting TiO2@MSMP exhibits an A-type crystalline polymorph and mean particle size of approximately 2 µm, displaying a type IV adsorption isotherm with a mean pore diameter of 19 nm and an average surface area of 12.34 m2/g. The adsorption ability of TiO2@MSMP towards methyl orange (MO) and crystal violet (CV) were 85.8 mg/g and 103.8 mg/g, respectively. The reusability of TiO2@MSMP was achieved by UV irradiation, which resulted in photodegradation of the adsorbed dye over 80 % while maintaining good absorption ability and structural stability during the recycling process. Given its cost-effectiveness, high adsorption capacity, and excellent reusability, TiO2@MSMP holds promise as an effective and environmentally friendly adsorbent with significant potential for removing dyes from aqueous solutions and purifying water.

Latent profile analysis of depression in US adults with obstructive sleep apnea hypopnea syndrome.

Objective: This study used latent profile analysis to explore the level of depression among US adults with obstructive sleep apnea hypopnea syndrome (OSAHS) symptoms and to identify different latent categories of depression to gain insight into the characteristic differences between these categories. Methods: The data of this study were obtained from the National Health and Nutrition Examination Survey (NHANES) database, and the subjects with OSAHS symptoms were aged 18 years and older. The latent profile analysis (LPA) method was used to fit the latent depression categories in subjects with OSAHS symptoms. The chi-square test, rank sum test, and binary logistic regression were used to analyze the influencing factors of depression subgroups in subjects with OSAHS symptoms. Results: Three latent profiles were identified: low-level (83.7%), moderate-level (14.5%) and high-level (1.8%) depression. The scores of 9 items in the high-level depression group were higher than those in the other two groups. Among them, item 4 "feeling tired or lack of energy" had the highest score in all categories. Conclusion: Depression in subjects with OSAHS symptoms can be divided into low-level, moderate-level and high-level depression. There are significant differences among different levels of depression in gender, marital status, PIR, BMI, smoking, general health condition, sleep duration and OSAHS symptom severity.

Psychometric evaluation of the Chinese version of the Scale of Effects of Social Media on Eating Behaviour and research of its influencing factors.

BACKGROUND: Social media has become an indispensable part of contemporary young people's lives, and the influence of social media on college students' eating and other health-related behaviors has become increasingly prominent. However, there is no assessment tool to determine the effects of social media on Chinese college students' eating behavior. This study aims to translate the Scale of Effects of Social Media on Eating Behaviour (SESMEB) into Chinese. Its applicability to Chinese college students was examined through reliability and validity indexes, and the influencing factors of SESMEB were explored. METHODS: The questionnaire survey included 2374 Chinese college students. The Brislin translation model was used to translate the original scale into Chinese. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to test the construct validity of the scale, and the content validity of the scale was assessed through the content validity index. The internal consistency of the scale was assessed by calculating Cronbach's alpha coefficient, McDonald's Omega coefficient, split-half reliability, and test-retest reliability. Multiple stepwise linear regression analysis was performed to identify potential influences on the effects of social media on eating behavior. RESULTS: EFA supported the one-factor structure, and the factor loadings of each item on this dimension were higher than 0.40. CFA showed good model fitness indexes. The content validity index of the scale was 0.94. The Cronbach's alpha coefficient and McDonald's Omega coefficient for the scale were 0.964, the split-half reliability coefficient was 0.953, and the test-retest reliability was 0.849. Gender, education, major, frequency of social media use, online sexual objectification experiences, fear of negative evaluations, and physical appearance perfectionism explained 73.8% of the variance in the effects of social media on eating behavior. CONCLUSIONS: The Chinese version of the SESMEB has good psychometric properties and is a valid measurement tool for assessing the effects of social media on college students' eating behavior. Subjects who were female, highly educated, non-medical, had frequent social media use, online sexual objectification experiences, fear of negative evaluations, and physical appearance perfectionism used social media to have a higher impact on eating behavior.

Discovery of novel JAK1 inhibitors through combining machine learning, structure-based pharmacophore modeling and bio-evaluation.

BACKGROUND: Janus kinase 1 (JAK1) plays a critical role in most cytokine-mediated inflammatory, autoimmune responses and various cancers via the JAK/STAT signaling pathway. Inhibition of JAK1 is therefore an attractive therapeutic strategy for several diseases. Recently, high-performance machine learning techniques have been increasingly applied in virtual screening to develop new kinase inhibitors. Our study aimed to develop a novel layered virtual screening method based on machine learning (ML) and pharmacophore models to identify the potential JAK1 inhibitors. METHODS: Firstly, we constructed a high-quality dataset comprising 3834 JAK1 inhibitors and 12,230 decoys, followed by establishing a series of classification models based on a combination of three molecular descriptors and six ML algorithms. To further screen potential compounds, we constructed several pharmacophore models based on Hiphop and receptor-ligand algorithms. We then used molecular docking to filter the recognized compounds. Finally, the binding stability and enzyme inhibition activity of the identified compounds were assessed by molecular dynamics (MD) simulations and in vitro enzyme activity tests. RESULTS: The best performance ML model DNN-ECFP4 and two pharmacophore models Hiphop3 and 6TPF 08 were utilized to screen the ZINC database. A total of 13 potentially active compounds were screened and the MD results demonstrated that all of the above molecules could bind with JAK1 stably in dynamic conditions. Among the shortlisted compounds, the four purchasable compounds demonstrated significant kinase inhibition activity, with Z-10 being the most active (IC50 = 194.9 nM). CONCLUSION: The current study provides an efficient and accurate integrated model. The hit compounds were promising candidates for the further development of novel JAK1 inhibitors.

1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism.

The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1H-indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC50 values of 0.43-3.88 µM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G2/M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo. Therefore, 3-amino-1H-indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.

Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.

Impacts of organic loading rate and hydraulic retention time on organics degradation, interspecies interactions and functional traits in thermophilic anaerobic co-digestion of food waste and sewage sludge.

This study provided novel insights into the effects of organic loading rate (OLR) and hydraulic retention time (HRT) on thermophilic anaerobic co-digestion of food waste and sewage sludge. The obtained maximum methane (CH4) yield of 328 ± 4 mL CH4/g CODfed at HRT of 15 days (OLR = 5.8 g VS/L/d) was partly attributable to the enhanced acidogenesis, acetogenesis, and methanogenesis phases. The increased key enzyme activities, particularly acetate kinase (improved by 5.2-fold), providing substantial methanogenic substrates for efficient CH4 production. The functional syntrophs that were related to syntrophic decarboxylation, novel acetate oxidation & reductive acetyl-CoA, and ß-oxidation pathways could drive trophic interactions with methanogens. This markedly stimulated hydrogenotrophic Methanoculleus thermophilus metabolism and concomitantly enriched mixotrophic Methanosarcina thermophila. The distinctive cross-feeding interspecies interactions significantly affected the assembly and dynamics of thermophilic consortia. These findings shed light on the physicochemical and microbial mechanisms of HRT- and OLR-dependent enhancement of methanogenesis.

Bilberry Anthocyanins (Vaccinium myrtillus L.) Induced Apoptosis of B16-F10 Cells and Diminished the Effect of Dacarbazine.

Anthocyanins have been reported to have potential as dietary or pharmaceutical supplements in the application of cancer prevention and adjunctive treatment. However, there are few studies on the effect of anthocyanins on melanoma, which have only been performed in cell lines. The objective of this work was to investigate the anticancer effects and mechanisms of bilberry anthocyanin extract (BAE) on melanoma In Vitro and In Vivo. Moreover, a primary study was done to investigate how BAE influenced C57BL/6 mice bearing subcutaneous B16-F10 tumors treated with dacarbazine (DTIC). BAE-induced apoptosis in B16-F10 cells was associated with activation of the mitochondrial pathway induced by increased reactive oxygen species. More, In Vivo anticancer activity studies indicated that BAE attenuated melanoma growth, as identified by hematoxylin-eosin staining, Ki-67, and TUNEL assays. Further western blot results revealed higher phospho-Akt expression with the combination of BAE and DTIC, indicating no suppression of the PI3K/AKT signaling pathway. In summary, this study demonstrated the anti-melanoma activity of BAE and investigated its mechanism. Notably, it should be careful to use products enriching BAE for those melanoma patients treated with DTIC.

Protection of adipose-derived mesenchymal stromal cells during acute lung injury requires autophagy maintained by mTOR.

Previous studies suggest that mesenchymal stem cells may represent a promising cellular therapy for acute lung injury (ALI); however, the underlying relevant molecular mechanisms remain unclear. Adipose-derived mesenchymal stem cells (ADSCs) were isolated and characterized by alizarin red staining, oil red staining, and flow cytometry. Lung injury and inflammatory cell infiltration were determined using the Evans blue method, wet/dry weight ratio, and H&E staining. An ELISA was used to detect the concentrations of IFN-γ, IL-2, and TNF-α. Autophagy was detected with an mRFP-GFP-LC3 dual-fluorescence autophagy indicator system, Western blotting, and electron microscopy. We first demonstrated that ADSCs did alleviate the inflammatory responses and tissue damage in lipopolysaccharide (LPS)-induced ALI. Next, we further demonstrated in vivo that autophagy plays a key role in the maintenance of ADSC therapeutic efficacy. In vitro experiments demonstrated that ADSCs co-cultured with alveolar epithelial cells depend on autophagy for significant anti-inflammatory functions. Moreover, the mammalian target of rapamycin (mTOR) is a key regulator of autophagy. Taken together, our findings demonstrate that the effect of ADSC on ALI, especially on alveolar epithelial cells, is dependent on mTOR-mediated autophagy maintenance. The significance of our study for ALI therapy is discussed with respect to a more complete understanding of the therapeutic strategy paradigm.

Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer.

VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro, as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC50: 0.084 ± 0.04 µM, Dmax: 73.7%) and HUVEC cells (DC50: 0.51 ± 0.10 µM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G2/M phase cycle arrest and apoptosis. All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.

Design, synthesis and biological evaluation of coumarin derivatives as potential BRD4 inhibitors.

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.

Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors.

Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 µM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 µM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.

Baculovirus infection induces disruption of the nuclear lamina.

Baculovirus nucleocapsids egress from the nucleus primarily via budding at the nuclear membrane. The nuclear lamina underlying the nuclear membrane represents a substantial barrier to nuclear egress. Whether the nuclear lamina undergoes disruption during baculovirus infection remains unknown. In this report, we generated a clonal cell line, Sf9-L, that stably expresses GFP-tagged Drosophila lamin B. GFP autofluorescence colocalized with immunofluorescent anti-lamin B at the nuclear rim of Sf9-L cells, indicating GFP-lamin B was incorporated into the nuclear lamina. Meanwhile, virus was able to replicate normally in Sf9-L cells. Next, we investigated alterations to the nuclear lamina during baculovirus infection in Sf9-L cells. A portion of GFP-lamin B localized diffusely at the nuclear rim, and some GFP-lamin B was redistributed within the nucleus during the late phase of infection, suggesting the nuclear lamina was partially disrupted. Immunoelectron microscopy revealed associations between GFP-lamin B and the edges of the electron-dense stromal mattes of the virogenic stroma, intranuclear microvesicles, and ODV envelopes and nucleocapsids within the nucleus, indicating the release of some GFP-lamin B from the nuclear lamina. Additionally, GFP-lamin B phosphorylation increased upon infection. Based on these data, baculovirus infection induced lamin B phosphorylation and disruption of the nuclear lamina.

Minocycline exerts multiple inhibitory effects on vascular endothelial growth factor-induced smooth muscle cell migration: the role of ERK1/2, PI3K, and matrix metalloproteinases.

Widely used tetracycline antibiotics affect many cellular functions relevant to human vascular disease including cell proliferation, migration, and matrix remodeling. We examined whether minocycline inhibited human aortic smooth muscle cell (HASMC) migration induced by vascular endothelial growth factor (VEGF). After the establishment of an optimal dose, minocycline treated HASMC were exposed to VEGF. HASMC migration, matrix metalloproteinase (MMP)-2 and MMP-9 activities, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) phosphorylation were determined by smooth muscle cell (SMC) invasion assay, real-time polymerase chain reaction, zymograms, and Western blot analysis, respectively. We demonstrated that VEGF and platelet-derived growth factor (PDGF)-induced SMC migration in a dose-dependent manner. MMP-9, but not MMP-2, mRNA was increased during VEGF stimulation. MMP-9 activity was increased from 1.5- to 2.5-fold in a dose-dependent manner (P<0.05). Both ERK1/2 and PI3K/AKt pathways were activated during VEGF-induced HASMCs migration. We then demonstrated that minocycline can inhibit VEGF-induced HASMC migration (P<0.05). The effects may be through the inhibition of MMP-9 mRNA transcription, protein activities and downregulation of ERK1/2 and PI3K/Akt pathway phosphorylation. Our results indicated that minocycline exerts multiple effects on VEGF-induced SMC migration, including inhibition of MMP-9 mRNA transcription and protein activities and downregulating ERK1/2 and PI3K signal pathways, suggesting minocycline may be a potentially therapeutic approach to inhibit disease process induced angiogenesis.