Molecular recognition of morphine and fentanyl by the human µ-opioid receptor.

Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of µ-opioid receptor (µOR). Here, we report structures of the human µOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of µOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of µOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of µOR, which may facilitate rational design of next-generation analgesics.

Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Summer heatwaves promote harmful algal blooms in the Fuchunjiang Reservoir, an important drinking water source.

Extensive outbreaks of harmful algal blooms (HABs) occurred in the Fuchunjiang Reservoir in 2022, a crucial urban drinking water source, coinciding with extreme summer heatwaves. We hypothesize that these heatwaves contributed to HABs formation and expansion. Leveraging Landsat 8 and Sentinel-2 data, we employed clustering and machine learning methods to quantify the HABs distribution and area. Concurrent meteorological and water quality data aided in uncovering the effects of heatwave on HABs. When applying different methods to extract HABs from remote sensing images, random forest (RF) analyses indicated accuracies of 99.3% and 99.8% for Landsat 8 and Sentinel-2 data, respectively, while classification and regression tree (CART) analyses indicated 99.1% and 99.7% accuracies, respectively. Support vector machine (SVM) exhibited lower accuracies (83.5% and 97.4%). Thus RF, given its smaller differences between satellites and high accuracy, was selected for further analysis. Both satellites detected extensive HABs in 2022, with Sentinel-2 recording a peak area of 24.13 km2 (44.6% of cloud-free water area) on August 11, 2022. Increasing trends with amplified durations were observed for summer heatwaves in Jiande and Tonglu around the Fuchunjiang Reservoir. Notably, these areas experienced extreme heatwaves for 63 and 58 days in 2022, respectively, more than double the 1980-2022 average. From June 1 to October 8, 2022, water temperature peaks significantly coincided with expansive HABs and elevated chlorophyll a (Chl-a) concentration from 4.8 µg/L to 119.2 µg/L during the summer heatwaves. Our findings indicated that the reservoir became more HAB-prone during heatwave events, escalating the drinking water safety risk. These results emphasize the challenges faced by reservoir managers in dealing with climate-induced extreme heatwaves and underscore the urgency for heightened attention from water source management departments.

Multi-color UCNPs/CsPb(Br1-xIx)3 for upconversion luminescence and dual-modal anticounterfeiting.

Advanced hybrid materials have attracted extensive attention in optoelectronics and photonics application due to their unique and excellent properties. Here, the multicolor upconversion luminescence properties of the hybrid materials composed of CsPbX3(X = Br/I) perovskite quantum dots and upconversion nanoparticles (UCNPs, core-shell NaYF4:25%Yb3+,0.5%Tm3+@NaYF4) is reported, achieving the upconversion luminescence with stable and bright of CsPbX3 perovskite quantum dots under 980 nm excitation. Compared with the nonlinear upconversion of multi-photon absorption in perovskite, UCNPs/CsPbX3 achieves lower power density excitation by using the UCNPs as the physical energy transfer level, meeting the demand for multi-color upconversion luminescence in optical applications. Also, the UCNPs/CsPbX3 combined with ultraviolet curable resin (UVCR) shows excellent water and air stability, which can be employed as multicolor fluorescent ink for screen printing security labels. Through the conversion strategy, the message of the security labels can be encrypted and decrypted by using UV light and a 980 nm continuous wave excitation laser as a switch, which greatly improves the difficulty of forgery. These findings provide a general method to stimulate photon upconversion and improve the stability of perovskite nanocrystals, which will be better applied in the field of anti-counterfeiting.

Dose-response association between transportation noise exposure and type 2 diabetes: A systematic review and meta-analysis of prospective cohort studies.

AIMS: To examine the longitudinal association between transportation noise exposure (road traffic, aircraft, and railway noise) and T2D in a meta-analysis. MATERIALS AND METHODS: We systematically searched PubMed, Embase, Scopus, Cochrane, and Web of Science published up to February 2022. The GRADE approach was used to evaluate the study quality, and the pooled effect estimate was calculated by the fixed-effects model or the random-effects model. RESULTS: We included 10 prospective studies with a total of 4,994,171 participants and 417,332 T2D cases in the meta-analysis. According to the Navigation guide, 8 studies out of 10 were rated as having a probably high or high risk of bias. For road noise, the pooled relative risk (RR) per 10 dB higher Lden for developing T2D was 1.06 (95% CI:1.03, 1.09) with high heterogeneity (I2  = 90.1%, p < 0.001). Similar associations were also observed in aircraft and railway noise: the pooled RR were separately were: 1.01 (1.00, 1.01) and 1.02 (1.01, 1.03) separately. A 'dose-response' analysis found a similar linear association between road noise exposure and the risk of T2D. CONCLUSIONS: An overall 6% increase in the risk of T2D per 10 dB increase in road exposure was observed. Further studies are needed to confirm our findings, especially for aircraft and railway noise, and to identify the mechanisms involved.

Association between serum calcium level and type 2 diabetes: An NHANES analysis and Mendelian randomization study.

AIMS: This study investigated the association between serum calcium levels and the prevalence of T2D using a cross-sectional study and Mendelian randomization analysis. METHODS: Cross-sectional data were obtained from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Serum calcium levels were divided into three groups (low, medium and high groups) according to the tertiles. Logistic regression was used to estimate the association between serum calcium levels and T2D prevalence. Instrumental variables for serum calcium levels were obtained from the UK Biobank and a two-sample MR analysis was performed to examine the causal relationship between genetically predicted serum calcium levels and the risk of T2D. RESULTS: A total of 39,645 participants were available for cross-sectional analysis. After adjusting for covariates, participants in the high serum calcium group had significantly higher odds of T2D (OR = 1.18, 95% CI = 1.07, 1.30, p = 0.001) than those in the moderate group. Restricted cubic spline plots showed a J-shaped curve relationship between serum calcium level and prevalence of T2D. Consistently, Mendelian randomization analysis showed that higher genetically predicted serum calcium levels were causally associated with a higher risk of T2D (OR = 1.16, 95% CI: 1.01, 1.33, p = 0.031). CONCLUSIONS: The results of this study suggest that higher serum calcium levels are causally associated with a higher risk of T2D. Further studies are needed to clarify whether intervening in high serum calcium could reduce the risk of T2D.

A tunable perfect absorber based on a black phosphorus/bowtie shaped cavity hybrid metasurface.

The practical application of black phosphorus (BP) is limited by its low absorption characteristics. In this work, we propose a perfect absorber based on a BP and bowtie shaped cavity, which has high tunability and excellent optical performance. This absorber effectively increases the light-matter interaction and achieves perfect absorption by using a monolayer BP and a reflector to form a Fabry-Perot cavity. We study the influence of structural parameters on the absorption spectrum and realize the adjustment of frequency and absorption in a certain range. Applying an external electric field on the surface of BP by electrostatic gating, we can change its carrier concentration to control its optical properties. In addition, we can flexibly tune the absorption and Q-factor by varying the polarization direction of incident light. This absorber has promising applications in optical switches, sensing, and slow light, which provides a new perspective for the practical application of BP and a foundation for future research, offering possibilities for more applications.

Living alone and the risk of depressive symptoms: a cross-sectional and cohort analysis based on the China Health and Retirement Longitudinal Study.

BACKGROUND: There were a few studies that examined the longitudinal association between living alone and depressive symptoms, and the vast majority of them were conducted in patients with certain diseases, such as heart failure, cancer, and glaucoma. This study aimed to examine the association between living alone and depressive symptoms in a large representative older Chinese population. METHODS: The China Health and Retirement Longitudinal Study (CHARLS) data from 2015 to 2018 were used. Living alone was defined as participants who did not live with others ever or more than 11 months in the past year at baseline. Depressive symptoms were measured using the 10-item Center for Epidemiological Studies-Depression Scale (CES-D10). The multivariate logistic regression was used to estimate the relationship between living alone and depressive symptoms. RESULTS: There were 5,311 and 2,696 participants ≥ 60 years old included in the cross-sectional and cohort analysis, respectively. The risk of depressive symptoms in participants who lived alone was significantly higher than those who lived with others in both cross-sectional (OR:1.33; 95%CI:1.14,1.54) and cohort analysis (OR:1.23; 95%CI:0.97,1.55). There was a significant interaction between financial support and living alone (Pinteraction = 0.008) on the risk of depressive symptoms. Stratified analyses showed that, compared to those who lived with others, the risk of depressive symptoms in participants who lived alone increased by 83% (OR:1.83; 95%CI:1.26,2.65) in participants receiving lower financial support. However, we did not find statistically significant associations in participants with medium (OR:1.10; 95%CI: 0.74,1.63) and higher financial support (OR: 0.87; 95%CI: 0.53,1.41). CONCLUSION: Living alone was associated with a higher risk of depressive symptoms in the Chinese older population, and this association was moderated by the receipt of financial support. Living alone may be an effective and easy predictor for early identification of high-risk populations of depression in the older population.

Environmental noise exposure and health outcomes: an umbrella review of systematic reviews and meta-analysis.

BACKGROUND: Environmental noise is becoming increasingly recognized as an urgent public health problem, but the quality of current studies needs to be assessed. To evaluate the significance, validity and potential biases of the associations between environmental noise exposure and health outcomes. METHODS: We conducted an umbrella review of the evidence across meta-analyses of environmental noise exposure and any health outcomes. A systematic search was done until November 2021. PubMed, Cochrane, Scopus, Web of Science, Embase and references of eligible studies were searched. Quality was assessed by AMSTAR and Grading of Recommendations, Assessment, Development and Evaluation (GRADE). RESULTS: Of the 31 unique health outcomes identified in 23 systematic reviews and meta-analyses, environmental noise exposure was more likely to result in a series of adverse outcomes. Five percent were moderate in methodology quality, the rest were low to very low and the majority of GRADE evidence was graded as low or even lower. The group with occupational noise exposure had the largest risk increment of speech frequency [relative risk (RR): 6.68; 95% confidence interval (CI): 3.41-13.07] and high-frequency (RR: 4.46; 95% CI: 2.80-7.11) noise-induced hearing loss. High noise exposure from different sources was associated with an increased risk of cardiovascular disease (34%) and its mortality (12%), elevated blood pressure (58-72%), diabetes (23%) and adverse reproductive outcomes (22-43%). In addition, the dose-response relationship revealed that the risk of diabetes, ischemic heart disease (IHD), cardiovascular (CV) mortality, stroke, anxiety and depression increases with increasing noise exposure. CONCLUSIONS: Adverse associations were found for CV disease and mortality, diabetes, hearing impairment, neurological disorders and adverse reproductive outcomes with environmental noise exposure in humans, especially occupational noise. The studies mostly showed low quality and more high-quality longitudinal study designs are needed for further validation in the future.

Protein phosphatase 1 catalyzes HBV core protein dephosphorylation and is co-packaged with viral pregenomic RNA into nucleocapsids.

Hepatitis B virus (HBV) replicates its genomic DNA via viral DNA polymerase self-primed reverse transcription of a RNA pre-genome in the nucleocapsid assembled by 120 core protein (Cp) dimers. The arginine-rich carboxyl-terminal domain (CTD) of Cp plays an important role in the selective packaging of viral DNA polymerase-pregenomic (pg) RNA complex into nucleocapsid. Previous studies suggested that the CTD is initially phosphorylated at multiple sites to facilitate viral RNA packaging and subsequently dephosphorylated in association with viral DNA synthesis and secretion of DNA-containing virions. However, our recent studies suggested that Cp is hyper-phosphorylated as free dimers and its dephosphorylation is associated with pgRNA encapsidation. Herein, we provide further genetic and biochemical evidence supporting that extensive Cp dephosphorylation does take place during the assembly of pgRNA-containing nucleocapsids, but not empty capsids. Moreover, we found that cellular protein phosphatase 1 (PP1) is required for Cp dephosphorylation and pgRNA packaging. Interestingly, the PP1 catalytic subunits α and ß were packaged into pgRNA-containing nucleocapsids, but not empty capsids, and treatment of HBV replicating cells with core protein allosteric modulators (CpAMs) promoted empty capsid assembly and abrogated the encapsidation of PP1 α and ß. Our study thus identified PP1 as a host cellular factor that is co-packaged into HBV nucleocapsids, and plays an essential role in selective packaging of the viral DNA-polymerase-pgRNA complex through catalyzing Cp dephosphorylation.

Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent.

5-Fluorouracil (5-FU) is a chemotherapeutic drug against many types of cancers, especially colorectal cancer. However, its short plasma half-life and serious adverse reactions limit its wide clinical applications. To overcome these shortcomings, a novel lipophilic 5-FU carbonate [XL-01, (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl tetradecyl carbonate] was designed, synthesized, and encapsulated into liposome (LipoXL-01) by a thin-film dispersion method through formulation screening and optimization. LipoXL-01 was characterized by a particle size of around 100 nm, polydispersity index of 0.200, ζ-potential value of -41 mV, encapsulation efficiency of 93.9%, and drug-loading efficiency of 11.6%. The cellular uptake of LipoXL-01 was increased in a concentration-dependent manner on HCT15 cells. LipoXL-01 could enhance the induction of cell apoptosis and the inhibition of cell migration and arrest the ability of the cell cycle at the S-phase on HCT15 cells better than 5-FU. Additionally, LipoXL-01 exhibited a slow drug release profile with a cumulative release rate of 12% in 8 h. The results of pharmacokinetic and biodistribution studies revealed that LipoXL-01 had a long plasma half-life (7.21 h) and a high tumor accumulation (733 nmol/g at 8 h). The in vivo antitumor effect study also showed that LipoXL-01 had more potent efficacy than 5-FU (65 vs 48% of the tumor-inhibition rate). Simultaneously, negligible systemic toxicity was observed via analyzing the body weight as well as hematological and pathological parameters in the tested mice. The current study suggested that LipoXL-01 might be a promising nanocandidate for chemotherapy of colorectal cancer.

Design, synthesis and biological evaluation of nitrofuran-1,3,4-oxadiazole hybrids as new antitubercular agents.

Three series of novel nitrofuran-1,3,4-oxadiazole hybrids were designed and synthesized as new anti-TB agents. The structure activity relationship study indicated that the linkers and the substituents on the oxadiazole moiety greatly influence the activity, and the substituted benzenes are more favoured than the cycloalkyl or heterocyclic groups. Besides, the optimal compound in series 2 was active against both MTB H37Rv strain and MDR-MTB 16883 clinical isolate and also displayed low cytotoxicity, low inhibition of hERG and good oral PK, indicating its promising potential to be a lead for further structural modifications.

Egg-based influenza split virus vaccine with monoglycosylation induces cross-strain protection against influenza virus infections.

Each year influenza virus infections cause hundreds of thousands of deaths worldwide and a significant level of morbidity with major economic burden. At the present time, vaccination with inactivated virus vaccine produced from embryonated chicken eggs is the most prevalent method to prevent the infections. However, current influenza vaccines are only effective against closely matched circulating strains and must be updated and administered yearly. Therefore, generating a vaccine that can provide broad protection is greatly needed for influenza vaccine development. We have previously shown that vaccination of the major surface glycoprotein hemagglutinin (HA) of influenza virus with a single N-acetylglucosamine at each of the N-glycosylation sites [monoglycosylated HA (HAmg)] can elicit better cross-protection compared with the fully glycosylated HA (HAfg). In the current study, we produced monoglycosylated inactivated split H1N1 virus vaccine from chicken eggs by the N-glycosylation process inhibitor kifunensine and the endoglycosidase Endo H, and intramuscularly immunized mice to examine its efficacy. Compared with vaccination of the traditional influenza vaccine with complex glycosylations from eggs, the monoglycosylated split virus vaccine provided better cross-strain protection against a lethal dose of virus challenge in mice. The enhanced antibody responses induced by the monoglycosylated vaccine immunization include higher neutralization activity, higher hemagglutination inhibition, and more HA stem selectivity, as well as, interestingly, higher antibody-dependent cellular cytotoxicity. This study provides a simple and practical procedure to enhance the cross-strain protection of influenza vaccine by removing the outer part of glycans from the virus surface through modifications of the current egg-based process.

STED microscopy reveals in-situ photoluminescence properties of single nanostructures in densely perovskite thin films.

All-inorganic perovskite nanomaterials have attracted much attention recently due to their prominent optical performance and potential application for optoelectronic devices. The carriers dynamics of all-inorganic perovskites has been the research focus because the understanding of carriers dynamics process is of critical importance for improving the fluorescence conversion efficiency. While photophysical properties of excited carrier are usually measured at the macroscopic scale, it is necessary to probe the in-situ dynamics process at the nanometer scale and gain deep insights into the photophysical mechanisms and their localized dependence on the thin-film nanostructures. Stimulated emission depletion (STED) nanoscopy with super-resolution beyond the diffraction limit can directly provide explicit information at a single particle level or nanometer scale. Through this unique technique, we firstly study the in-situ dynamics process of single CsPbBr3 nanocrystals(NCs) and nanostructures embedded inside high-dense samples. Our findings reveal the different physical mechanisms of PL blinking and antibunching for single CsPbBr3 NCs and nanostructures that correlate with thin-film nanostructural features (e.g. defects, grain boundaries and carrier mobility). The insights gained into such nanostructure-localized physical mechanisms are critically important for further improving the material quality and its corresponding device performance.

Impacts of irrigation efficiency on water-dependent sectors are heavily controlled by region-specific institutions and infrastructures.

Farmers' investment in more efficient irrigation systems represents a primary adaptation strategy when confronting climate change. However, the regional benefits of these investments and their influence on the conflicting demands among different water dependent stakeholders for intensely irrigated regions remains an open question. Using the Pacific Northwest of the United States as an illustrative region of focus, we show that higher irrigation efficiency has diverse effects across stakeholders that are contingent on many local climatic, institutional and infrastructural factors such as the availability of water storage, the location of hydropower generators, and water rights. These complexities limit simple abstractions of irrigation efficiency as broader policy challenge and are central to its inclusion within the class of "wicked problems". Additionally, we argue that the widely used rebound effect concept, which implicitly discourages irrigation efficiency supporting policies, should not be assumed to fully capture the nuances of the complex suite of regional impacts that emerge from irrigation efficiency investments. Consequently, the evaluation of irrigation efficiency investments requires a broader framing across a diversity of perspectives. policies and actions that are pluralistic, context-specific, and closely engage various groups of stakeholders in the policymaking process.

Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity.

A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28-0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.

Design, synthesis and antimycobacterial activity of new benzothiazinones inspired by rifampicin/rifapentine.

A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 µM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Design, synthesis and anti-HBV activity of NVR3-778 derivatives.

NVR3-778, one of the most advanced capsid assembly modulators (CAMs), is currently in phase II clinical trial for the treatment of HBV infection. In this study, we reported the first structure optimization of NVR3-778. Compound 2d was found to exhibit more potent anti-HBV activity (IC50: 0.25 µM), lower cytotoxicity (CC50: 10.68 µM) and higher selectivity index (SI: 40.72) than NVR3-778 (IC50: 0.33 µM; CC50: 5.14 µM; SI: 18.36) in vitro, and also display similar inhibitory effect on the assembly of HBV capsids as NVR3-778. Molecular docking further suggested that compound 2d might form a stronger interaction with core protein. Moreover, compound 2d also showed acceptable pharmacokinetic profiles. Currently compound 2d was selected as a new lead for further modifications, and studies to determine the in vivo anti-HBV studies of 2d will begin soon.

Screening and Identification of the Main Metabolites of Schisantherin a In Vivo and In Vitro by Using UHPLC-Q-TOF-MS/MS.

Schisantherin A is an active ingredient originating from Schisandra chinensis (Turcz.) which has hepatoprotective and anti-oxidation activities. In this study, in vitro metabolisms investigated on rat liver microsomes (RLMs) and in vivo metabolisms explored on male Sprague Dawley rats of Schisantherin A were tested, respectively. The metabolites of Schisantherin A were identified using ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Based on the method, 60 metabolites were successfully identified and structurally characterized including 48 phase-I and 12 phase-II metabolites. Among the metabolites, 45 metabolites were reported for the first time. Moreover, 56 and eight metabolites were detected in urine and bile and 19 metabolites were identified in rats' plasma. It demonstrated that hepatic and extra-hepatic metabolic pathways were both involved in Schisantherin A biotransformation in rats. Five in vitro metabolites were structurally characterized for the first time. The results indicated that the metabolic pathways mainly include oxidation, reduction, methylation, and conjugation with glucuronide, taurine, glucose, and glutathione groups. This study provides a practical strategy for rapidly screening and identifying metabolites, and the results provide basic data for future pharmacological and toxicology studies of Schisantherin A and other lignin ingredients.

Reciprocal loop of hypoxia-inducible factor-1α (HIF-1α) and metastasis-associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E-cadherin transcription.

Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1α (HIF-1α) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1α recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1α, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.