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Pesticides are widely used to control weeds and pests in agricultural settings but harm non-target aquatic organisms. In this study, our objective was to evaluate the effect of short-term exposure (one week) to environmentally relevant concentrations of pesticides mixture (low concentration: 0.4 μg/l atrazine, 0.5 μg/l Roundup®, and 0.5 μg/l 2,4-D; high concentration: 0.8 μg/l atrazine, 1 μg/l Roundup®, and 1 μg/l 2,4-D) on tissue architecture, body fluid conditions, and 3-nitrotyrosine protein (NTP) and Na+/K+-ATPase, expressions in tissues of American oyster (Crassostrea virginica) under controlled laboratory conditions. Histological analysis demonstrated the atrophy in the gills and digestive glands of oysters exposed to pesticides mixture. Periodic acid-Schiff (PAS) staining showed the number of hemocytes in connective tissue increased in low- and high-concentration pesticides exposure groups. However, pesticides treatment significantly (P < 0.05) decreased the amount of mucous secretion in the gills and digestive glands of oysters. The extrapallial fluid (i.e., body fluid) protein concentrations and glucose levels were dropped significantly (P < 0.05) in oysters exposed to high-concentration pesticides exposure groups. Moreover, immunohistochemical analysis showed significant upregulations of NTP and Na+/K+-ATPase expressions in the gills and digestive glands in pesticides exposure groups. Our results suggest that exposure to environmentally relevant pesticides mixture causes morphological changes in tissues and alters body fluid conditions and NTP and Na+/K+-ATPase expressions in tissues, which may lead to impaired physiological functions in oysters. [Display omitted] • Pesticides are widely used to control weeds and pests in agricultural settings. • Aquatic environments are becoming increasingly inundated by pesticides. • Pesticides harm non-target aquatic organisms. • Pesticides altered the morphology of gills and digestive glands of oysters. • Pesticides induced nitrative stress and Na+/K+-ATPase expression in oysters. [ABSTRACT FROM AUTHOR]

Abstract: Background: Carbon monoxide, the gaseous product of heme oxygenase, is a signalling molecule with a broad spectrum of biological activities. The aim of this study was to investigate the effects of carbon monoxide on proliferation of human pancreatic cancer. Methods: In vitro studies were performed on human pancreatic cancer cells (CAPAN-2, BxPc3, and PaTu-8902) treated with a carbon monoxide-releasing molecule or its inactive counterpart, or exposed to carbon monoxide gas (500ppm/24h). For in vivo studies, pancreatic cancer cells (CAPAN-2/PaTu-8902) were xenotransplanted subcutaneously into athymic mice, subsequently treated with carbon monoxide-releasing molecule (35mg/kg b.w. i.p./day), or exposed to safe doses of carbon monoxide (500ppm 1h/day; n =6 in each group). Results: Both carbon monoxide-releasing molecule and carbon monoxide exposure significantly inhibited proliferation of human pancreatic cancer cells (p <0.05). A substantial decrease in Akt phosphorylation was observed in carbon monoxide-releasing molecule compared with inactive carbon monoxide-releasing molecule treated cancer cells (by 30–50%, p <0.05). Simultaneously, carbon monoxide-releasing molecule and carbon monoxide exposure inhibited tumour proliferation and microvascular density of xenotransplanted tumours (p <0.01), and doubled the survival rates (p <0.005). Exposure of mice to carbon monoxide led to an almost 3-fold increase in carbon monoxide content in tumour tissues (p =0.006). Conclusion: These data suggest a new biological function for carbon monoxide in carcinogenesis, and point to the potential chemotherapeutic/chemoadjuvant use of carbon monoxide in pancreatic cancer. [Copyright &y& Elsevier]

Background & Aims: Hepatitis C virus (HCV) infection leads to progressive liver disease, frequently culminating in fibrosis and hepatocellular carcinoma. The mechanisms underlying liver injury in chronic hepatitis C are poorly understood. This study evaluated the role of vascular endothelial growth factor (VEGF) in hepatocyte polarity and HCV infection. Methods: We used polarized hepatoma cell lines and the recently described infectious HCV Japanese fulminant hepatitis (JFH)-1 cell culture system to study the role of VEGF in regulating hepatoma permeability and HCV infection. Results: VEGF negatively regulates hepatocellular tight junction integrity and cell polarity by a novel VEGF receptor 2–dependent pathway. VEGF reduced hepatoma tight junction integrity, induced a re-organization of occludin, and promoted HCV entry. Conversely, inhibition of hepatoma expressed VEGF with the receptor kinase inhibitor sorafenib or with neutralizing anti-VEGF antibodies promoted polarization and inhibited HCV entry, showing an autocrine pathway. HCV infection of primary hepatocytes or hepatoma cell lines promoted VEGF expression and reduced their polarity. Importantly, treatment of HCV-infected cells with VEGF inhibitors restored their ability to polarize, showing a VEGF-dependent pathway. Conclusions: Hepatic polarity is critical to normal liver physiology. HCV infection promotes VEGF expression that depolarizes hepatoma cells, promoting viral transmission and lymphocyte migration into the parenchyma that may promote hepatocyte injury. [Copyright &y& Elsevier]

Abstract: Pharmacophore modelling, docking and virtual screening have become important tool in drug discovery process. Serotonin 2C (5-HT2C) receptor ligands have got major attention for their therapeutic uses as antidepressant and anorectic agents. Two step pharmacophore and docking based virtual screening was done using 5-HT2C agonists. Two common feature pharmacophore directed virtual hits had submicromolar activity. Refined pharmacophore with excluded volumes was constructed and combined with homology model based docking. Best hit from this virtual screening showed IC50 of 20.1nM. Similarity search of this hit compound resulted more active ligand with 7.8nM activity. [Copyright &y& Elsevier]

[Display omitted] Recently developed medicated dressings target either bacterial or fungal infection only, which is not effective for the treatment of mixed infections common in diabetic foot ulcers (DFUs). This study aimed to develop advanced bioactive alginate-based dressings (films and wafers) to deliver therapeutically relevant doses of ciprofloxacin (CIP) and fluconazole (FLU) to target mixed bacterial and fungal infections in DFUs. The alginate compatibility with the drugs was confirmed by SEM, XRD, FTIR and texture analysis, while the medicated wafers showed better fluid handling properties than the films in the presence of simulated wound fluid. The dressings showed initial fast release of FLU followed by sustained release of CIP which completely eradicated E. coli , S. aureus , P. aeruginosa and reduced fungal load (C. albicans) by 10-fold within 24 h. Moreover, the medicated dressings were biocompatible (>70% cell viability over 72 h) with human primary adult keratinocytes and in-vitro scratch assay showed 65–68% wound closure within 7 days. [ABSTRACT FROM AUTHOR]

Objective: Soluble vascular endothelial growth factor receptor–1 (also know as soluble fms-like tyrosine kinase [sFlt]-1) is a key causative factor of preeclampsia. Resveratrol, a plant phytoalexin, has antiinflammatory and cardioprotective properties. We sought to determine the effect of resveratrol on sFlt-1 release. Study Design: Human umbilical vein endothelial cells, transformed human trophoblast-8 (HTR/SVneo)-8/SVneo trophoblast cells, or placental explants were incubated with cytokines and/or resveratrol. Conditioned media were assayed for sFlt-1 by enzyme-linked immunosorbent assay and cell proteins used for Western blotting. Results: Resveratrol inhibited cytokine-induced release of sFlt-1 from normal placental explants and from preeclamptic placental explants. Preincubation of human umbilical vein endothelial cells or HTR-8/SVneo cells with resveratrol abrogated sFlt-1 release. Resveratrol prevented the up-regulation of early growth response protein-1 (Egr-1), a transcription factor necessary for induction of the vascular endothelial growth factor receptor–1 gene and caused up-regulation of heme oxygenase–1, a cytoprotective enzyme found to be dysfunctional in preeclampsia. Conclusion: In summary, resveratrol can inhibit sFlt-1 release and up-regulate heme oxygenase–1; thus, may offer therapeutic potential in preeclampsia. [ABSTRACT FROM AUTHOR]

Abstract: The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt-1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. These findings provide strong evidence for a protective role of HO-1 in pregnancy and identify HO as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, thus, they have the potential to ameliorate early onset preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to assess cardiac function and cell damage in intrauterine growth-restricted (IUGR) fetuses across clinical Doppler stages of deterioration. Study Design: One hundred twenty appropriate-for-gestational-age and 81 IUGR fetuses were classified in stages 1/2/3 according umbilical artery present/absent/reversed end-diastolic blood flow, respectively. Cardiac function was assessed by modified-myocardial performance index, early-to-late diastolic filling ratios, cardiac output, and cord blood B-type natriuretic peptide; myocardial cell damage was assessed by heart fatty acid–binding protein, troponin-I, and high-sensitivity C-reactive protein. Results: Modified-myocardial performance index, blood B-type natriuretic peptide, and early-to-late diastolic filling ratios were increased in a stage-dependent manner in IUGR fetuses, compared with appropriate-for-gestational-age fetuses. Heart fatty acid–binding protein levels were higher in IUGR fetuses at stage 3, compared with control fetuses. Cardiac output, troponin-I, and high-sensitivity C-reactive protein did not increase in IUGR fetuses at any stage. Conclusion: IUGR fetuses showed signs of cardiac dysfunction from early stages. Cardiac dysfunction deteriorates further with the progression of fetal compromise, together with the appearance of biochemical signs of cell damage. [Copyright &y& Elsevier]

Alkali-activated binders have been widely used as they are low-carbon materials and eco-friendly to environment. Compressive strength (CS) is the most crucial parameter for designing the alkali-activated binder (AAB) concrete. Hence, the accurate prediction of CS becomes the most important when considering the issues like time saving and cost benefits analytical point of view. This study adopted the conventional deep learning (CDL) and hybrid deep learning (HDL) models to enhance the prediction of CS through analyzing the experimental CS data collected from previous research articles. Three CDL models such as CNN, GRU and LSTM, and their hybrid HDL forms like CNN-GRU, CNN-LSTM and LSTM-GRU were employed to predict the CS property. The models were run with 2060 data points including eight input parameters of AAB concrete specimens, where the 70% data points were used for training and 30% for testing phases. It was observed that HDL models showed the better prediction performance than the CDL models, where the hybrid CNN-LSTM model presents the significant accurate prediction of strength property, with R 2 = 0.997, RMSE = 1.45 and R 2 = 0.995, RMSE = 2.24 for training and testing phases, respectively. Moreover, SHAP analysis of CNN-LSTM model exhibits that age of concrete specimens is the main dominant parameter for strength development and cement contents is the second highest contributing issue to strength increment of alkali-activated concrete. These results might be applied in the field of building construction sectors for optimum design of alkali-activated concrete specimens for better strength achievement. • Alkali-activated materials strength is predicted using Deep learning approaches. • Hybrid CNN-LSTM model shows better prediction accuracy. • Parametric analysis is performed with SHAP algorithm. • Uncertainty analysis is done for checking the overfitting of the models. [ABSTRACT FROM AUTHOR]

• Hybrid geothermal PCM solar flat plate collector dryer can continuously operate. • The system has 20.5% higher efficiency than conventional flat plate solar collector. • The maximum and average outlet temperature of the system are 60.59 °C and 47.24 °C. • Sensitivity and convergence analysis proves the accuracy of mathematical model. • Proposed dryer can reduce the 20% energy consumed for drying in food industry. Drying techniques reduce post-harvest food deterioration. However, conventional drying consumes 20–25% of the energy used in food processing industries. This work presents a detailed design and comprehensive numerical analysis of a hybrid geothermal-PCM flat plate solar collector, which is in effect a self-sustaining renewable energy food drying system. The applicability of the hybrid geothermal-solar dryer for developing countries with a significant underground geothermal temperature gradient is investigated. The performed numerical analysis promises high efficiency and effectivity of this near-zero hybrid energy technology. The proposed conceptual design assessed using the related mathematical model to assess the functional parameters of the hybrid geothermal PCM flat plate solar collector dryer. Numerical simulation showed that the efficiency of hybrid geothermal PA-FPSC is 20.5% higher than conventional flat plate solar collector when the mass flow rate is at 0.02 kg/s. Therefore, successful integration of this technology to the existing food processing industries of the developing countries could be a step towards the prevention of irreversible climate change achieving SDG 12 (sustainable development goals). [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) signaling is tightly regulated by specific VEGF receptors (VEGF-R). Recently, we identified heterodimerisation between VEGFR-1 and VEGFR-2 (VEGFR 1–2 ) to regulate VEGFR-2 function. However, both the mechanism of action and the relationship with VEGFR-1 homodimers remain unknown. The current study shows that activation of VEGFR 1–2 , but not VEGFR-1 homodimers, inhibits VEGFR-2 receptor phosphorylation under VEGF stimulation in human endothelial cells. Furthermore, inhibition of phosphatidylinositol 3-kinase (PI3K) increases VEGFR-2 phosphorylation under VEGF stimulation. More importantly, inhibition of PI3K pathway abolishes the VEGFR 1–2 mediated inhibition of VEGFR-2 phosphorylation. We further demonstrate that inhibition of PI3K pathway promotes capillary tube formation. Finally, the inhibition of PI3K abrogates the inhibition of in vitro angiogenesis mediated by VEGFR 1–2 heterodimers. These findings demonstrate that VEGFR 1–2 heterodimers and not VEGFR-1 homodimers inhibit VEGF-VEGFR-2 signaling by suppressing VEGFR-2 phosphorylation via PI3K pathway. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) decreases bioavailability of nitric oxide (NO) and impairs NO-dependent relaxations. Like NO, hydrogen sulfide (H 2 S) is an antioxidant and vasodilator; however, the effect of ROS on H 2 S-induced relaxations is unknown. Here we investigated whether ROS altered the effect of H 2 S on vascular tone in mouse aorta and determined whether resveratrol (RVT) protects it via H 2 S. Pyrogallol induced ROS formation. It also decreased H 2 S formation and relaxation induced by l -cysteine and in mouse aorta. Pyrogallol did not alter sodium hydrogensulfide (NaHS)-induced relaxation suggesting that the pyrogallol effect on l -cysteine relaxations was due to endogenous H 2 S formation. RVT inhibited ROS formation, enhanced l -cysteine-induced relaxations and increased H 2 S level in aortas exposed to pyrogallol suggesting that RVT protects against “H 2 S-dysfunctions” by inducing H 2 S formation. Indeed, H 2 S synthesis inhibitor AOAA inhibited the protective effects of RVT. RVT had no effect on Ach-induced relaxation that is NO dependent and the stimulatory effect of RVT on H 2 S-dependent relaxation was also independent of NO. These results demonstrate that oxidative stress impairs endogenous H 2 S-induced relaxations and RVT offers protection by inducing H 2 S suggesting that targeting endogenous H 2 S pathway may prevent vascular dysfunctions associated by oxidative stress. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (EDF) reflects pathophysiological changes in the phenotype and functions of endothelial cells that result from and/or contribute to a plethora of cardiovascular diseases. We review the role of hydrogen sulfide (H 2 S) in the pathogenesis of EDF, one of the fastest advancing research topics. Conventionally treated as an environment pollutant, H 2 S is also produced in endothelial cells and participates in the fine regulation of endothelial integrity and functions. Disturbed H 2 S bioavailability has been suggested to be a novel indicator of EDF progress and prognosis. EDF manifests in different forms in multiple pathologies, but therapeutics aimed at remedying altered H 2 S bioavailability may benefit all. [ABSTRACT FROM AUTHOR]

Introduction High soluble Flt1 (sFlt1) is pivotal in the development of ‘preeclampsia phenotype’ of hypertension and proteinuria. Disruption of endogenous protective pathways and increased oxidative stress are hallmarks.of preeclampsia. Yet the underlying molecular mechanisms remains unclear. During high oxidative stress, thiols on key proteins are reversibly modified by S-glutathionylation, which can be enzymatically removed by Glutaredoxin-1(Glrx). We investigated the role of Glrx in preeclampsia. Results Glrx mRNA and protein expression were increased while -SSG adducts were lower in placenta from early onset preeclamptic (<34 wks) compared to gestational matched placenta (35 wks). During pregnancy mice overexpressing Glrx (TG) developed the “preeclampsia phenotype” with worse maternal and fetal outcome including; hypertension (day17.5), marked collapsed of glomeruli indicating kidney dysfunction and decreased placental weight compared to wildtype littermates. sFlt1 levels were higher in TG plasma and placenta. Thiol modification of key proteins that are part of the endogenous protective pathways regulating placenta sFlt1 expression were identified by Tandem Mass Tag analysis in endothelial cells overexpressing Glrx and confirmed by Biotin switch assay in placenta. Summary These data support the proposed hypothesis that Glrx regulates sFlt1 expression to promote the ‘PE phenotype’. [ABSTRACT FROM AUTHOR]