Anhydrous volatile fatty acid extraction through omniphobic membranes by hydrophobic deep eutectic solvents: Mechanistic understanding and future perspective.

Volatile fatty acids (VFAs) derived from arrested anaerobic digestion (AD) can be recovered as a valuable commodity for value-added synthesis. However, separating VFAs from digestate with complex constituents and a high-water content is an energy-prohibitive process. This study developed an innovative technology to overcome this barrier by integrating deep eutectic solvents (DESs) with an omniphobic membrane into a membrane contactor for efficient extraction of anhydrous VFAs with low energy consumption. A kinetic model was developed to elucidate the mechanistic differences between this novel omniphobic membrane-enabled DES extraction and the previous hydrophobic membrane-enabled NaOH extraction. Experimental results and mechanistic modeling suggested that VFA extraction by the DES is a reversible adsorption process facilitating subsequent VFA separation via anhydrous distillation. High vapor pressure of shorter-chain VFAs and low Nernst distribution coefficients of longer-chain VFAs contributed to DES-driven extraction, which could enable continuous and in-situ recovery and conversion of VFAs from AD streams.

Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFß1R1 inhibitor.

The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer. AIM: To investigate the impact of JOSD2 on the progression of ESCC. METHODS: Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry. RESULTS: Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5. CONCLUSION: JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.

Not so fast: Paradoxically increased variability in the glucose tolerance test due to food withdrawal in continuous glucose-monitored mice.

OBJECTIVE: This study was performed to determine the effect of fasting on reproducibility of the glucose tolerance test. Due to individual variation in animal feeding behaviors, fasting animals prior to metabolic and behavioral experiments is widely held to reduce inter-subject variation in glucose and metabolic parameters of preclinical rodent models. Reducing variability is especially important for studies where initial metabolite levels can influence the magnitude of experimental interventions, but fasting also imposes stress that may distort the variables of interest. One such intervention is the glucose tolerance test (GTT) which measures the maximum response and recovery following a bolus of exogenous glucose. We sought to investigate how fasting affects the response of individual mice to a GTT. METHODS: Using simultaneous continuous glucose monitoring (CGM) and indirect calorimetry, we quantified blood glucose, physical activity, body temperature, metabolic rates, and food consumption levels on a minute-to-minute basis in adult male mice for 4 weeks. We tested the effects of a 4-h or 18-h fast on the GTT to examine the effect of food withdrawal in light or dark photoperiods. Studies were also performed with 4-h fasting in additional mice without implanted CGM probes. RESULTS: Contrary to our expectations, a 4-h fast during the light photoperiod promotes a paradoxical increase in inter-animal variation in metabolic rate, physical activity, body temperature, glycemia, and glucose tolerance. This hyperglycemic and hyper-metabolic phenotype promotes increased corticosterone levels and is consistent with a behavioral stress response to food deprivation, even in well-fed mice. We find that mice undergoing an 18-h fast entered torpor, a hibernation-like state. In addition to low body temperature and metabolic rate, torpor is also associated with glucose levels 56 mg/dl lower than those seen in mice with ad libitum access to food. Moreover, the time spent in torpor affects the response to a GTT. CONCLUSION: Our results suggest fasting mice before glucose tolerance testing, and perhaps other experiments, can have the opposite of the intended effect where fasting can increase, rather than decrease, experimental variability.

Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors.

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.

Coupling physical selection with biological selection for the startup of a pilot-scale, continuous flow, aerobic granular sludge reactor without treatment interruption.

This study removes two technical constraints for transitioning full-scale activated sludge infrastructure to continuous flow, aerobic granular sludge (AGS) facilities. The first of these is the loss of treatment capacity as a result of the rapid washout of flocculent sludge inventory and in turn the potential loss of nitrification during initial AGS reactor startup. The second is the physical selector design which currently is limited to either the complex sequencing batch reactor selection or sidestream hydrocyclones. Briefly, real wastewater data collected from this study suggested that by increasing the surface overflow rate (SOR) of an upflow clarifier to 10 m h - 1, the clarifier can be taken advantage of as a physical selector to separate flocculant sludge from AGS. Redirecting the physical selector underflow and overflow sludge to the feast and famine zones of a treatment train, respectively, can create a biological selection that not only promotes AGS formation but also safeguards the effluent quality throughout the AGS reactor startup period. This study provides a novel concept for economically implementing continuous flow AGS within existing full-scale, continuous flow treatment trains.

Autophagy Inhibition Contributes to Apoptosis of PLK4 Downregulation-induced Dormant Cells in Colorectal Cancer.

Dormant cancer cells account for cancer recurrence, distant metastasis and drug resistance which lead to poor prognosis in colorectal cancer (CRC). However, little is known about the molecular mechanisms regulating tumor cell dormancy and how to eliminate dormant cancer cells. Recent studies indicate autophagy affects dormant tumor cell survival. Here, we found that polo-like kinases 4 (PLK4), a central regulator of the cell cycle and proliferation, plays a crucial role in regulating CRC cells dormancy both in vitro and in vivo. Downregulation of PLK4 induced dormancy and inhibited migration and invasion in different CRC cell lines. Clinically, PLK4 expression was correlated with the dormancy markers (Ki67, p-ERK, p-p38) and late recurrence in CRC tissues. Mechanistically, downregulation of PLK4 induced autophagy contributed to restoring phenotypically aggressive tumor cells to a dormant state through the MAPK signaling pathway, and inhibition of autophagy would trigger apoptosis of dormant cells. Our findings reveal that downregulation of PLK4-induced autophagy contributes to tumor dormancy and autophagy inhibition leads to apoptosis of CRC dormant cells. Our study is the first to report that downregulation PLK4 induced autophagy is an early event in CRC dormancy and highlights autophagy inhibitor as a potential therapeutic target for dormant cell elimination.

Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells.

Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.

Unblocking the rate-limiting step of the municipal sludge anaerobic digestion.

Anaerobic digestion stabilizes municipal sludge through total solids reduction and biogas production. It is generally accepted that hydrolysis accounts for the rate-limiting step of municipal sludge anaerobic digestion, impacting the overall rates of solids reduction and methane production. Technically, the sludge hydrolysis rate can be enhanced by the application of thermal hydrolysis pretreatment (THP) and is also affected by the total solids concentration, temperature, and solids retention time used in the anaerobic digestion. This study systematically analyzed and compared ways to take these four factors into the consideration of modern anaerobic digestion system for achieving the maximum solid reduction. Results showed that thermophilic anaerobic digestion was superior to mesophilic anaerobic digestion in terms of solids reduction but vice versa in terms of the methane production when integrated with THP. This difference has to do with the intermediate product accumulation and inhibition when hydrolysis outpaced methanogenesis in THP-enhanced thermophilic anaerobic digestion, which can be mitigated by adjusting the solids retention time. PRACTITIONER POINTS: THP followed by TAD offers the greatest solids reduction rate. THP followed by MAD offered the greatest methane production rate. FAN inhibition appears to be an ultimate limiting factor constraining the methane production rate. In situ ammonia removal technique should be developed to further unblock the rate-limiting step.

Pivotal role of municipal wastewater resource recovery facilities in urban agriculture: A review.

Urban agriculture provides a promising, comprehensive solution to water, energy, and food scarcity challenges resulting from the population growth, urbanization, and the accelerating effects of anthropogenic climate change. Their close access to consumers, profitable business models, and important roles in educational, social, and physical entertainment benefit both developing and developed nations. In this sense, Urban Water Resource Reclamation Facilities (WRRFs) can play a pivotal role in the sustainable implementation of urban agriculture. Reclaimed water as a recovered resource has less supply variability and in certain cases can be of higher quality than other water sources used in agriculture. Another recovered resource, namely, biosolids, as byproduct from wastewater treatment can be put to beneficial use as fertilizers, soil amendments, and construction material additives. The renewable electricity, heat, CO2 , and bioplastics produced from WRRFs can also serve as essential resources in support of urban agriculture operation with enhanced sustainability. In short, this review exhibits a holistic picture of the state-of-the-art of urban agriculture in which WRRFs can potentially play a pivotal role. PRACTITIONER POINTS: Reclaimed water can be of higher quality than other sources used in urban agriculture. Biosolids can be put to beneficial use as fertilizers, soil amendments, and construction material additives. The renewable electricity, heat, CO2 , and bioplastics produced can also serve as essential resources in support of urban agriculture.

PAT2 regulates vATPase assembly and lysosomal acidification in brown adipocytes.

OBJECTIVE: Brown adipocytes play a key role in maintaining body temperature as well as glucose and lipid homeostasis. However, brown adipocytes need to adapt their thermogenic activity and substrate utilization to changes in nutrient availability. Amongst the multiple factors influencing brown adipocyte activity, autophagy is an important regulatory element of thermogenic capacity and activity. Nevertheless, a specific sensing mechanism of extracellular amino acid availability linking autophagy to nutrient availability in brown adipocytes is unknown. METHODS: To characterize the role of the amino acid transporter PAT2/SLC36A2 in brown adipocytes, loss or gain of function of PAT2 were studied with respect to differentiation, subcellular localization, lysosomal activity and autophagy. Activity of vATPase was evaluated by quenching of EGFP fused to LC3 or FITC-dextran loaded lysosomes in brown adipocytes upon amino acid starvation, whereas the effect of PAT2 on assembly of the vATPase was investigated by Native-PAGE. RESULTS: We show that PAT2 translocates from the plasma membrane to the lysosome in response to amino acid withdrawal. Loss or overexpression of PAT2 impair lysosomal acidification and starvation-induced S6K re-phosphorylation, as PAT2 facilitates the assembly of the lysosomal vATPase, by recruitment of the cytoplasmic V1 subunit to the lysosome. CONCLUSIONS: PAT2 is an important sensor of extracellular amino acids and regulator of lysosomal acidification in brown adipocytes.

Poorer Survival in Patients with Cecum Cancer Compared with Sigmoid Colon Cancer.

Background and Objectives: An increasing number of studies have shown the influence of primary tumor location of colon cancer on prognosis, but the prognostic difference between colon cancers at different locations remains controversial. After comparing the prognostic differences between left-sided and right-sided colon cancer, the study subdivided left-sided and right-sided colon cancer into three parts, respectively, and explored which parts had the most significant prognostic differences, with the aim to further analyze the prognostic significance of primary locations of colon cancer. Materials and Methods: Clinicopathological data of patients with colon cancer who underwent radical surgery from the Surveillance, Epidemiology, and End Results Program database were analyzed. The data was divided into two groups (2004−2009 and 2010−2015) based on time intervals. Two tumor locations with the most significant survival difference were explored by using Cox regression analyses. The prognostic difference of the two locations was further verified in survival analyses after propensity score matching. Results: Patients with right-sided colon cancer had worse cancer-specific and overall survival compared to left-sided colon cancer. Survival difference between cecum cancer and sigmoid colon cancer was found to be the most significant among six tumor locations in both 2004−2009 and 2010−2015 time periods. After propensity score matching, multivariate analyses showed that cecum cancer was an independent unfavorable factor for cancer specific survival (HR [95% CI]: 1.11 [1.04−1.17], p = 0.001 for 2004−2009; HR [95% CI]: 1.23 [1.13−1.33], p < 0.001 for 2010−2015) and overall survival (HR [95% CI]: 1.09 [1.04−1.14], p < 0.001 for 2004−2009; HR [95% CI]: 1.09 [1.04−1.14], p < 0.001 for 2010−2015) compared to sigmoid colon cancer. Conclusions: The study indicates the prognosis of cecum cancer is worse than that of sigmoid colon. The current dichotomy model (right-sided vs. left-sided colon) may be inappropriate for the study of colon cancer.

Exosome-delivered miR-221/222 exacerbates tumor liver metastasis by targeting SPINT1 in colorectal cancer.

MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR-221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR-221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR-221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR-221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.

In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC).

Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.

Prognosis model of colorectal cancer patients based on NOTCH3, KMT2C, and CREBBP mutations.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers. The aim of our study was to explore its related mutations, identify novel mutation markers, and construct predictive models for postoperative CRC patients, so as to provide evidence for the diagnosis, treatment, and prognosis of CRC. METHODS: A total 50 CRC patients were collected, and the mutations in tissue samples were detected through next-generation sequencing (NGS). Meanwhile, 246 CRC cases with complete mutation data were downloaded from The Cancer Genome Atlas (TCGA) database. Afterwards, the co-mutations in both clinical and TCGA cohorts were identified, and the high-frequency mutation genes were selected. Subsequently, functional enrichment analysis was performed, and overall survival (OS) and progression-free survival (PFS) predictive models were constructed. RESULTS: In all, 18 out of 238 co-mutation genes mutated in at least 20% of the samples and were selected out as common high-frequency mutation genes. They were significantly enriched in 460 Gene Ontology (GO) terms and 87 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P<0.05), which were closely related to the occurrence and development of CRC. Among the 18 genes, NOTCH3, histone lysine methyltransferase 2C (KMT2C), and cAMP-response element binding protein-BP (CREBBP) were respectively associated with tumor position, stage, and PFS (P<0.05), and could be considered as potential biomarkers of CRC. Finally, OS and PFS predictive models were constructed and verified using the 50 clinical cases, with both models demonstrating high fitting degrees useful for predicting the OS and PFS of CRC patients. CONCLUSIONS: NOTCH3, KMT2C, and CREBBP were found to be prospective biomarkers for the diagnosis and prognosis of CRC. The prognosis prediction models had high sensitivity and could be used to predict the OS and PFS of CRC patients.

First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo.

A growing number of reports suggested that the inhibitor targeting cyclin-dependent kinases (CDK) 2/4/6 can act as a more feasible chemotherapy strategy. In the present paper, a novel PROTAC molecule was developed based on the structure of Ribociclib's derivative. In malignant melanoma cells, the degrader can not only degrade CDK 2/4/6 simultaneously and effectively, but also remarkably induce cell cycle arrest and apoptosis of melanoma cells. Moreover, PROTAC molecules with CRBN ligands always have poor oral bioavailability. We developed the orally bioavailable prodrug for the first time. It would provide general solution for oral administration of the PROTAC molecules, derived from CRBN ligands, for animal test conveniently.

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis.

OBJECTIVE: Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. The objective of this study was to determine whether integrin activity can regulate insulin sensitivity in adipocytes and thereby systemic metabolism. METHODS: We characterized integrin activity in adipose tissue and its consequences on whole-body metabolism using adipose-selective deletion of ß1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre) in mice. RESULTS: We demonstrate that integrin signaling regulates white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in a lipodystrophy-like phenotype and systemic insulin resistance. However, brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. CONCLUSIONS: Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole-body metabolism.

lncRNA-SNHG17 promotes colon adenocarcinoma progression and serves as a sponge for miR-375 to regulate CBX3 expression.

Long non-coding RNA (lncRNA) has been reported could regulate initiation and progression of colon adenocarcinoma (COAD) tumorigenesis in recent years. Small nucleolar RNA host gene 17 (SNHG17) was found play crucial roles in cancer progression but its role in COAD remains unclear. In this work, qRT-PCR was performed to detect SNHG17 expression level in COAD cell lines. Roles of SNHG17 on COAD cell behaviors were analyzed with gain and loss-of-function experiments. Luciferase activity assay, RNA pull-down assay, and RNA immunoprecipitant assay were performed to analyze the association of SNHG17 or chromobox 3 (CBX3) with microRNA-375 (miR-375). Effects of SNHG17 on miR-375/CBX3 axis were analyzed by rescue experiments. We showed SNHG17 was upregulated expression in COAD tissues and cells. Functionally, SNHG17 could promote COAD cell proliferation, colony formation, migration, and invasion in vitro. Further investigations showed SNHG17 serves as competing endogenous RNA (ceRNA) for miR-375 to regulate CBX3 expression. Additionally, we showed the roles of SNHG17 on COAD cell behaviors were exerted via miR-375/CBX3 axis. In conclusion, we demonstrated a novel SNHG17/miR-375/CBX3 triplets that participates in COAD progression, which may provide promising therapeutic targets for COAD.

Long noncoding RNA LINC01578 drives colon cancer metastasis through a positive feedback loop with the NF-κB/YY1 axis.

Metastasis accounts for poor prognosis of cancers and related deaths. Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play critical roles in several types of cancer. However, which lncRNAs contribute to metastasis of colon cancer is still largely unknown. In this study, we found that lncRNA LINC01578 was correlated with metastasis and poor prognosis of colon cancer. LINC01578 was upregulated in colon cancer, associated with metastasis, advanced clinical stages, poor overall survival, disease-specific survival, and disease-free survival. Gain-of-function and loss-of-function assays revealed that LINC01578 enhanced colon cancer cell viability and mobility in vitro and colon cancer liver metastasis in vivo. Mechanistically, nuclear factor kappa B (NF-κB) and Yin Yang 1 (YY1) directly bound to the LINC01578 promoter, enhanced its activity, and activated LINC01578 expression. LINC01578 was shown to be a chromatin-bound lncRNA, which directly bound NFKBIB promoter. Furthermore, LINC01578 interacted with and recruited EZH2 to NFKBIB promoter and further repressed NFKBIB expression, thereby activating NF-κB signaling. Through activation of NF-κB, LINC01578 further upregulated YY1 expression. Through activation of the NF-κB/YY1 axis, LINC01578 in turn enhanced its own promoter activity, suggesting that LINC01578 and NF-κB/YY1 formed a positive feedback loop. Blocking NF-κB signaling abolished the oncogenic roles of LINC01578 in colon cancer. Furthermore, the expression levels of LINC01578, NFKBIB, and YY1 were correlated in clinical tissues. Collectively, this study demonstrated that LINC01578 promoted colon cancer metastasis via forming a positive feedback loop with NF-κB/YY1 and suggested that LINC01578 represents a potential prognostic biomarker and therapeutic target for colon cancer metastasis.

Design and synthesis of novel Flavone-based histone deacetylase inhibitors antagonizing activation of STAT3 in breast cancer.

Histone deacetylases (HDACs) inhibitors have demonstrated a great clinical achievement in hematological malignancies. However, the efficacy of HDACs inhibitors in treating solid tumors remains limited due to the complicated tumor microenvironment. In this study, we designed and synthesized a class of novel HDACs inhibitors based on the structure of flavones and isoflavones, followed by biological evaluation. To be specific, a lead compound 15a was discovered with strong anti-proliferative effects on a variety of solid tumor cells, especially for breast cancer cells with resistance to SAHA. Studies demonstrated that 15a could significantly inhibit the activity of HDAC 1, 2, 3 (class I) and 6 (class IIB), leading to a dose-dependent accumulation of acetylated histones and α-Tubulin, cell cycle arrest (G1/S phase) and apoptosis in breast cancer cells. Furthermore, the lead compound 15a could also antagonize the activation of STAT3 induced by HDACs inhibition in some breast cancer cells, which further reduced the level of pro-survive proteins in tumor cells and enhanced anti-tumor activity regulated by STAT3 signaling in vivo. Overall, our findings demonstrated that the novel compound 15a might be a HDACs inhibitor candidate, which could be used as promising chemotherapeutic agent for breast cancer.