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Exploring novel p-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors has become one of the most promising research directions in herbicide innovation. On the basis of our tremendous interest in exploiting more powerful HPPD inhibitors, we designed a family of benzyl-containing triketone-aminopyridines via a structure-based drug design (SBDD) strategy and then synthesized them. Among these prepared derivatives, the best active 3-hydroxy-2-(3,5,6-trichloro-4-((4-isopropylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one (23, IC50 = 0.047 μM) exhibited a 5.8-fold enhancement in inhibiting Arabidopsis thaliana (At) HPPD activity over that of commercial mesotrione (IC50 = 0.273 μM). The predicted docking models and calculated energy contributions of the key residues for small molecules suggested that an additional π-π stacking interaction with Phe-392 and hydrophobic contacts with Met-335 and Pro-384 were detected in AtHPPD upon the binding of the best active compound 23 compared with that of the reference mesotrione. Such a molecular mechanism and the resulting binding affinities coincide with the proposed design scheme and experimental values. It is noteworthy that inhibitors 16 (3-hydroxy-2-(3,5,6-trichloro-4-((4-chlorobenzyl)amino)picolinoyl)cyclohex-2-en-1-one), 22 (3-hydroxy-2-(3,5,6-trichloro-4-((4-methylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one), and 23 displayed excellent greenhouse herbicidal effects at 150 g of active ingredient (ai)/ha after postemergence treatment. Furthermore, compound 16 showed superior weed-controlling efficacy against Setaria viridis (S. viridis) versus that of the positive control mesotrione at multiple test dosages (120, 60, and 30 g ai/ha). These findings imply that compound 16, as a novel lead of HPPD inhibitors, possesses great potential for application in specifically combating the malignant weed S. viridis.

Herbicide resistance has become one of the foremost problems in crop production worldwide. New herbicides are required to manage weeds that have evolved resistance to the existing herbicides. However, relatively few herbicides with new modes of action (MOAs) have been discovered in the past two decades. Therefore, the discovery of new herbicides (i.e., new chemical classes or MOAs) remains a primary but ongoing strategy to overcome herbicide resistance and ensure crop production. In this mini-review, starting with the inherent characteristics of the target proteins and the inhibitor structures, we propose two strategies for the rational design of new herbicides and one computational method for the risk evaluation of target mutation-conferred herbicide resistance. The information presented here may improve the utilization of known targets and inspire the discovery of herbicides with new targets. We believe that these strategies may trigger the sustainable development of herbicides in the future. © 2021 Society of Chemical Industry.

Boron-modified high-ortho phenolic resins (BPRs) were prepared under normal pressure by using phenol and formaldehyde as raw materials, zinc acetate, and oxalic acid as catalysts, and boric acid as a modifier. Boron-modified phenolic fibers (BPFs) were prepared by melt spinning and curing in a mixture of formaldehyde and hydrochloric acid, followed by a heat treatment under high temperature. The structure, ortho–para ratio (O/P), molecular weight and distribution, spinnability, thermal stability, fiber strength, and morphology of the resins were characterized by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and fiber strength testing. The results showed that the addition of boric acid reduced the ortho reaction of the synthetic resin and the O/P value of phenolic resin. When the content of boric acid was 3 wt%, the thermal stability was the best, the O/P value was up to 3.26, and the weight average molecular weight (Mw) was 18745 g/mol. In Compared with the unmodified resin, the mass loss was increased by 33.7%, and finally the carbon yield was 51.2%. The tensile strength of the fibers reached 187.2 MPa and the elongation at break was 10.5%. By introducing boron into the molecular chain, the structure of the resin was improved, and the thermal stability and mechanical properties of the fibers were improved.

Background Maternal obesity is an emerging problem in the modern world. Growing evidence suggests that intrauterine high-fat (HF) exposure may predispose progeny to subsequent metabolic challenges. Progeny born to mothers who ate an HF diet also tends to eat an HF diet when growing and aggravate metabolic issues. Thus, the generational transmission of obesity is cyclical. Developing a strategy to prevent the occurrence of metabolic syndrome related to prenatal and/or postnatal HF diet is important. In this study, the reprogramming effects of maternal resveratrol treatment for the progeny with maternal HF/postnatal HF diets were investigated. Methods Sprague-Dawley dams were fed either a control or a high-fat/high sucrose diet (HFHS) from mating to lactation. After weaning, the progeny was fed chow or an HF diet. Four experimental groups were yielded: CC (maternal/postnatal control diet), HC (maternal HF/postnatal control diet), CH (maternal control/postnatal HFHS diet), and HH (maternal/postnatal HFHS diet). A fifth group (HRH) received a maternal HFHS diet plus maternal resveratrol treatment and a postnatal chow diet to study the effects of maternal resveratrol therapy. Results Maternal resveratrol treatment lessened the weight and adiposity of progeny that were programmed by combined prenatal and postnatal HFHS diets. Maternal resveratrol therapy ameliorated the decreased abundance of the sirtuin 1 (SIRT1) enzyme in retroperitoneal tissue and the altered leptin/soluble leptin receptor ratio of progeny. Maternal resveratrol therapy also decreased lipogenesis and increased lipolysis for progeny. Conclusions Maternal resveratrol intervention can prevent adiposity programmed by maternal and postnatal HFHS diets by inducing lipid metabolic modulation. This study offers a novel reprogramming role for the effect of maternal resveratrol supplements against obesity.

New 8-chloro-2-phenyl-2,7-naphthyridin-1(2H)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based N-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2H)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, 17c (IC50,MET of 13.8 nM) or 17e (IC50,AXl of 17.2 nM) and 17i (IC50,AXl of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.

Background: Circular RNAs (circRNA) play an essential role in the tumorigenesis of non-small cell lung cancer (NSCLC). CircDTL is a novel identified circRNA with little information regarding its biological role. However, the role of circDTL in NSCLC has not been investigated yet.Method: In this study, the levels of circDTL in tissues and cells were measured by RT-PCR. Cell viability was measured by the CCK-8 assay. Cell migration and invasion were evaluated using the wound healing assay and transwell assay, respectively. Cell death was measured by the cell death ELISA kit. The levels of Fe2+, ROS, MDA and GSH were measured using the commercial kits. The interactions between miR-1287-5p and circDTL/3′UTR GPX4 were verified by dual-luciferase activity assay. The effects of circDTL on tumor growth were evaluated in vivo.Results: CircDTL was found to be upregulated and acted as an oncogene in NSCLC cells. Knockdown of circDTL promoted both apoptosis and ferroptosis of NSCLC cells. It was identified that circDTL exerts its oncogenic effects via the circDTL/miR-1287-5p/GPX4 axis and GPX4 inhibits both ferroptosis and apoptosis. Finally, this study showed that silencing of circDTL promoted the sensitivity of NSCLC cells to chemotherapeutic agents and inhibited the growth of tumors in vivo.Conclusion: CircDTL acts as an oncogene and exerts its effects via the miR-1287-5p/GPX4 axis in NSCLC, providing a potential therapeutic target for NSCLC cancer therapy.

The γ-secretase complex is a presenilin-dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ-secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ-secretase complex inhibitor and CD147-directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ-secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Oxidative stress, nutrient-sensing signals, high-fat (HF) intake and dysbiosis of gut microbiota are involved in the development of hypertension, a disorder that can originate in early life. We examined whether postnatal HF diet can aggravate maternal NG-nitro-L-arginine-methyl ester (L-NAME) treatment-induced programmed hypertension and whether resveratrol therapy can prevent it. Pregnant Sprague–Dawley rats received L-NAME administration at 60 mg/kg/day subcutaneously during pregnancy alone, or with additional resveratrol (R) 50 mg/L in drinking water during the pregnancy and lactation. The offspring were onto either regular chow or HF diet (D12331) from weaning to 16 weeks of age. Male offspring rats were assigned to five groups (N=8/group): control, L-NAME, HF, L-NAME+HF and L-NAME+HF + R at weaning at 3 weeks of age. Rats were sacrificed at 16 weeks of age. We observed that postnatal HF diet exacerbates maternal L-NAME treatment-induced programmed hypertension in male adult offspring, which resveratrol attenuated. Combined L-LAME and HF diet-induced hypertension is related to increased oxidative stress, inhibiting AMP-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) pathway and altered gut microbiota compositions. L-NAME+HF caused an increase of the Firmicutes to Bacteroidetes ratio, which resveratrol therapy prevented. Additionally, the abundances of phylum Verrucomicrobia and genus Akkermansia were amplified by resveratrol therapy. Conclusively, our data highlighted the interactions between maternal NO deficiency, HF diet, AMPK/PGC-1α pathway and gut microbiota in which the blood pressure of adult offspring can be modified by resveratrol. Resveratrol might be a useful reprogramming strategy to prevent L-NAME and HF diet-induced hypertension of developmental origin.

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin–angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.

Rui Yu,1 Yefen Lu,2 Ren Yu,3 Jianjun Xie,4 Shoujun Zhou4 1Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, People’s Republic of China; 2Department of Neurology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, People’s Republic of China; 3Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, People’s Republic of China; 4Suzhou Science & Technology Town Hospital, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, People’s Republic of ChinaCorrespondence: Shoujun Zhou Email zsj201909@163.comBackground: Renal cell carcinoma (RCC) is a common urological system malignancy lack of effective therapeutic options. Upregulation of the Bcl-2 proteins was correlated with poor prognosis of RCC, suggesting that BH-3 mimetics may be a promising treatment option. ABT-263 is a BH3 mimetic that possesses anti-tumor effects. TW-37 is another inhibitor of Bcl-2 family protein with potential anti-tumor activities. However, since their effect as single agent is limited, combination treatment represents a strategy to improve the efficiency. We studied the ABT-263 in combination with TW-37 and analyzed the molecular mechanisms of action in RCC cells.Methods: MTT and colony formation assays were used to measure the proliferation of RCC cells. Transwell assay was used to assay the migration and invasion of RCC cells. Cell cycle distribution and apoptosis were measured using the flow cytometry and apoptotic nucleosome assay, respectively. Western blotting was performed to measure the change of proteins. The anti-tumor effects of ABT-263, TW-37 and their combination were also evaluated in vivo.Results: Cotreatment of TW-37 and ABT-263 synergistically repressed the proliferation of RCC cells. TW-37 and ABT-263 also synergistically inhibited the migration and invasion of RCC cells It was also showed that TW-37 and ABT-263 synergistically induced cell cycle arrest at the G2/M phase. Furthermore, increased apoptosis was observed after exposure to TW-37 and ABT-263. Mechanism investigation showed that TW-37 and ABT-263 synergistically induced apoptosis via the mitochondrial pathway and relied on the activation of Bax and caspases. Furthermore, ERK signaling pathway activation was detected after treated with TW-37 and ABT-263. Finally, TW-37 and ABT-263 also synergistically repressed the growth of RCC cells in xenograft mice.Conclusion: In summary, our data demonstrated that combined treatment with TW-37 and ABT-263 exhibited synergistic RCC cell death and this combination may be applied as an effective therapeutic strategy against RCC.Keywords: renal cell carcinoma; RCC, TW-37, ABT-263, apoptosis, ERK signaling

The persistence of macrophage-derived foam cells in the artery wall fuels atherosclerosis development. However, the mechanism of foam cell formation regulation remains elusive. We are committed to determining the role that CD147 might play in macrophage foam cell formation during atherosclerosis. In this study, we found that CD147 expression was primarily increased in mouse and human atherosclerotic lesions that were rich in macrophages and could be upregulated by ox-LDL. High-throughput compound screening indicated that ox-LDL-induced CD147 upregulation in macrophages was achieved through PI3K/Akt/mTOR signaling. Genetic deletion of macrophage CD147 protected against foam cell formation by impeding cholesterol uptake, probably through the scavenger receptor CD36. The opposite effect was observed in primary macrophages isolated from macrophage-specific CD147-overexpressing mice. Moreover, bioinformatics results indicated that CD147 suppression might exert an atheroprotective effect via various processes, such as cholesterol biosynthetic and metabolic processes, LDL and plasma lipoprotein clearance, and decreased platelet aggregation and collagen degradation. Our findings identify CD147 as a potential target for prevention and treatment of atherosclerosis in the future.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been recognized as one of the most promising targets in the field of herbicide innovation considering the severity of weed resistance currently. In a persistent effort to develop effective HPPD-inhibiting herbicides, a structure-guided strategy was carried out to perform the structural optimization for triketone-quinazoline-2,4-diones, a novel HPPD inhibitor scaffold first discovered in our lab. Herein, starting from the crystal structure of Arabidopsis thaliana (At)HPPD complexed with 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione (MBQ), three subseries of quinazoline-2,4-dione derivatives were designed and prepared by optimizing the hydrophobic interactions between the side chain of the core structure at the R1 position and the hydrophobic pocket at the active site entrance of AtHPPD. 6-(2-Hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(3-(trimethylsilyl)prop-2-yn-1-yl)quinazoline-2,4(1H,3H)-dione (60) with the best inhibitory activity against AtHPPD was identified to be the first subnanomolar-range AtHPPD inhibitor (Ki = 0.86 nM), which significantly outperformed that of the lead compound MBQ (Ki = 8.2 nM). Further determination of the crystal structure of AtHPPD in complex with compound 60 (1.85 A) and the binding energy calculation provided a molecular basis for the understanding of its high efficiency. Additionally, the greenhouse assay indicated that 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-propylquinazoline-2,4(1H,3H)-dione (28) and compound 60 showed acceptable crop safety against peanut and good herbicidal activity with a broad spectrum. Moreover, compound 28 also showed superior selectivity for wheat at the dosage of 120 g ai/ha and favorable herbicidal efficacy toward the gramineous weeds at the dosage of as low as 30 g ai/ha. We believe that compounds 28 and 60 have promising prospects as new herbicide candidates for wheat and peanut fields.

In the past decades, quinazoline-2,4-dione has attracted appreciable attention in the fields of medicinal and pesticide chemistry owing to its characteristic structure and multiple promising pharmacological properties. This review covers the rational design process, optimization details, and crop safety evaluation of a class of novel 4-hydroxyphenylpyruvate dioxygenase inhibitors featuring quinazoline-2,4-dione scaffold. Some analogues exhibit potent and broad-spectrum weed control. Besides, they also show favorable safety for the specific crops. Fortunately, a highly selective herbicide, Benquitrione, for controlling some frequent malignant weeds in sorghum fields was successfully screened out in this series, which has entered the registration and industrialization stage.

Huxie Huaji (HXHJ) Ointment is a famous traditional Chinese medicinal prescription and is commonly used for the clinical treatment of hepatocellular carcinoma by boosting immunity and detoxification. However, the scientific evidence for the effect of HXHJ Ointment on hepatocellular carcinoma and the underlying molecular mechanism are lacking. The present study aimed to identify the effects of HXHJ Ointment on hepatocellular carcinoma in vitro and in vivo as well as investigating the mechanistic basis for the anticancer effect of HXHJ ointment. First, liquid chromatography-mass spectrometry was used to verify the composition of HXHJ Ointment and quality control. Second, in vitro, Cell Counting Kit (CCK8) cell viability assay and Hoechst 33342 staining assay were performed to explain the cell apoptosis. The protein levels of tumor suppressor protein (p53), B-cell lymphoma 2 gene (Bcl-2), cytochrome C (Cyt-C), and aspartate proteolytic enzyme-3 (caspase-3) were examined by immunofluorescence. Finally, in vivo, hematoxylin and eosin (H&E) staining was used to observe the pathological changes in hepatocellular carcinoma samples. Western blots and immunohistochemistry were used to detect the anticancer properties of HXHJ ointment. The results in vitro showed that 20% HXHJ Ointment serum could significantly inhibit HepG2 cell proliferation, increased tumor suppressor gene p53, downregulated antiapoptotic protein Bcl-2, promoted the release of mitochondrial Cyt-C, activated caspase-3, and induced HepG2 cell apoptosis. Furthermore, in vivo experiments showed that HXHJ Ointment could effectively inhibit tumor growth in nude mice xenotransplanted with HepG2 cells, changed the morphology of tumor cells, and regulated the expression of apoptosis-related protein pathway p53/Bcl-2/Cyt-C/caspase-3. HXHJ Ointment can significantly inhibit the development of hepatocellular carcinoma, and its mechanism may be related to the regulation of p53/Bcl-2/Cyt-C/caspase-3 signaling pathway to induce cell mitochondrial apoptosis.

Diaryl ether (DE) is a functional scaffold existing widely both in natural products (NPs) and synthetic organic compounds. Statistically, DE is the second most popular and enduring scaffold within the numerous medicinal chemistry and agrochemical reports. Given its unique physicochemical properties and potential biological activities, DE nucleus is recognized as a fundamental element of medicinal and agrochemical agents aimed at different biological targets. Its drug-like derivatives have been extensively synthesized with interesting biological features including anticancer, anti-inflammatory, antiviral, antibacterial, antimalarial, herbicidal, fungicidal, insecticidal, and so on. In this review, we highlight the medicinal and agrochemical versatility of the DE motif according to the published information in the past decade and comprehensively give a summary of the target recognition, structure-activity relationship (SAR), and mechanism of action of its analogues. It is expected that this profile may provide valuable guidance for the discovery of new active ingredients both in drug and pesticide research.

Gut microbiota-dependent metabolites, in particular trimethylamine (TMA), are linked to hypertension. Maternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or consumption of food high in fructose (HFR) can induce hypertension in adult offspring. We examined whether 3,3-maternal dimethyl-1-butanol (DMB, an inhibitor of TMA formation) therapy can protect adult offspring against hypertension arising from combined HFR and TCDD exposure. Pregnant Sprague&ndash, Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) throughout pregnancy and lactation. Additionally, the pregnant dams received TCDD (200 ng/kg BW orally) or a corn oil vehicle on days 14 and 21 of gestation, and days 7 and 14 after birth. Some mother rats received 1% DMB in their drinking water throughout pregnancy and lactation. Six groups of male offspring were studied (n = 8 for each group): regular chow (CV), high-fructose diet (HFR), regular diet+TCDD exposure (CT), HFR+TCDD exposure (HRT), high-fructose diet+DMB treatment (HRD), and HFR+TCDD+DMB treatment (HRTD). Our data showed that TCDD exacerbates HFR-induced elevation of blood pressure in male adult offspring, which was prevented by maternal DMB administration. We observed that different maternal insults induced distinct enterotypes in adult offspring. The beneficial effects of DMB are related to alterations of gut microbiota, the increase in nitric oxide (NO) bioavailability, the balance of the renin-angiotensin system, and antagonization of aryl hydrocarbon receptor (AHR) signaling. Our findings cast new light on the role of early intervention targeting of the gut microbiota-dependent metabolite TMA, which may allow us to prevent the development of hypertension programmed by maternal excessive fructose intake and environmental dioxin exposure.

Carbon materials have attracted increasing attention for hydrogen storage due to their great specific surface areas, low weights, and excellent mechanical properties. However, the performance of carbon materials for hydrogen absorption is hindered by weak physisorption. To improve the hydrogen absorption performance of carbon materials, nanoporous structures, doped heteroatoms, and decorated metal nanoparticles, among other strategies, are adopted to increase the specific surface area, number of hydrogen storage sites, and metal catalytic activity. Herein, Li–fluorine codoped porous carbon nanofibers (Li–F–PCNFs) were synthesized to enhance hydrogen storage performance. Especially, perfluorinated sulfonic acid (PFSA) polymers not only served as a fluorine precursor, but also inhibited the agglomeration of lithium nanoparticles during the carbonization process. Li–F–PCNFs showed an excellent hydrogen storage capacity, up to 2.4 wt% at 0 °C and 10 MPa, which is almost 24 times higher than that of the pure porous carbon nanofibers. It is noted that the high electronegativity gap between fluorine and lithium facilitates the electrons of the hydrogen molecules being attracted to the PCNFs, which enhanced the hydrogen adsorption capacity. In addition, Li–F–PCNFs may have huge potential for application in fuel cells.

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin&ndash, angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague&ndash, Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.

Carboxylesterases (CEs) exist as multiple types of isomers in humans, and two major types are CE1 and CE2. They are widely distributed in human tissues and well-known for their important roles in drug metabolism and pathology of various diseases. Thus, the detection of CEs in living systems could provide efficient proof in disease diagnostics, as well as important information regarding chemotherapeutic effects of antitumor drugs and prognosis. To develop a specific probe to discriminate CEs from other hydrolases, especially cholinesterases, is quite challenging due to their structural similarities and substrate specificity. To date, almost all of the fluorescent probes developed for CEs have been constructed with an acetyl group as the recognition unit. Herein we proposed a new design strategy of probe-cavity matching, which led to the identification of a new fluorogenic substrate (termed as HBT-CE) with high specificity toward both CE isomers and improved sensitivity, considering the higher binding affinity and catalysis efficiency. The promising capability of HBT-CE was further demonstrated for endogenous CEs imaging in living cells, zebrafish, and nude mice. In addition, HBT-CE was successfully applied in kinetically monitoring drug-induced CE regulation in cancer cells. All of these findings suggest that HBT-CE is a valuable tool for tracking and imaging endogenous CEs in complex biological systems.

To examine the effects of maternal resveratrol in rats borne to dams with gestational high-fat diet (HFD)/obesity with or without postnatal high-fat diet. We first tested the effects of maternal resveratrol intake on placenta and male fetus brain in rats borne to dams with gestational HFD/obesity. Then, we assessed the possible priming effect of a subsequent insult, male offspring were weaned onto either a rat chow or a HFD. Spatial learning and memory were assessed by Morris water maze test. Blood pressure and peripheral insulin resistance were examined. Maternal HFD/obesity decreased adiponectin, phosphorylation alpha serine/threonine-protein kinase (pAKT), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF) in rat placenta, male fetal brain, and adult male offspring dorsal hippocampus. Maternal resveratrol treatment restored adiponectin, pAKT, and BDNF in fetal brain. It also reduced body weight, peripheral insulin resistance, increased blood pressure, and alleviated cognitive impairment in adult male offspring with combined maternal HFD and postnatal HFD. Maternal resveratrol treatment restored hippocampal pAKT and BDNF in rats with combined maternal HFD and postnatal HFD in adult male offspring dorsal hippocampus. Maternal resveratrol intake protects the fetal brain in the context of maternal HFD/obesity. It effectively reduced the synergistic effects of maternal HFD/obesity and postnatal HFD on metabolic disturbances and cognitive impairment in adult male offspring. Our data suggest that maternal resveratrol intake may serve as an effective therapeutic strategy in the context of maternal HFD/obesity.

Although usually self-limiting, Mycoplasma pneumoniae pneumonia (MPP) may lead to clinical or radiological deterioration despite macrolide antibiotic therapy, resulting in the development of refractory MPP (RMPP). Corticosteroids have been used to treat RMPP with beneficial effects. Serum lactate dehydrogenase (LDH) is a suggested biomarker for the use of steroid therapy. Since serum LDH is a non-specific marker and elevated in many inflammatory processes, this study investigates the predicting level of LDH isoenzymes for RMPP. Fifty-four children with non-refractory M. pneumoniae pneumonia (NRMPP) and 16 children with RMPP were enrolled in this study. In comparison to the NRMPP group, the RMPP group showed significantly higher levels of serum LDH. Concerning LDH isoenzymes, the RMPP group showed significantly lower proportions of LDH1 and LDH2, while higher LDH4 and LDH5 percentage. Receiver operating characteristic curve analysis showed that the area under the curve for the total LDH data was 0.812 with a cut-off of 408 IU/L (sensitivity of 75.0%, specificity of 72.2%). The areas under the curve for LDH4, LDH5, and [LDH4 + LDH5] were estimated to be 0.813, 0.818, and 0.829, respectively. The threshold for [LDH4 + LDH5] was estimated to be 109.4 IU/L (sensitivity, 75.0%; specificity, 87.0%). These results indicate that for the initiation of corticosteroid therapy, serum [LDH4 + LDH5] level is a more sensitive biomarker than total LDH. Key Words: children, LDH isoenzyme, refractory Mycoplasma pneumoniae pneumonia

Salmonella is one of the most common pathogenic bacterium, which causes food spoilage and human diseases. The national standard detection method (GB4789.4) and other fast detection methods for Salmonella cannot satisfy the requirements in the present climate because of their inefficiency, low accuracy, high equipment requirements, or high cost. In this study, we combine isothermal recombinase polymerase amplification (RPA) with unmodified gold nanoparticles (AuNPs) to detect Salmonella in milk. A rapid, effective, visualized, and low-cost RPA-AuNP assay was developed, with a detection limit of 50 CFU for milk samples after enrichment for 6 h or 1 pg for DNA within 15 min at 37 °C using simple water bath equipment. Furthermore, it exhibited no cross-reactions with other pathogens by using highly specific region of invA of Salmonella as the target detection gene. And it may apply to the local food inspection and detection center whose equipment conditions are poor.

The accurate quantification of p53 protein expression level is of great importance for cancer diagnosis. Here, a highly sensitive fluorescent sensor based on DNA functionalized magnetic nanoparticles was developed for the detection of p53 protein expression. Instead of a monoclonal antibody, a consensus DNA was employed to capture p53 protein. Meanwhile the fluorescent dye tethered DNA was used as the signal output instead of enzyme tagged nanoparticle or antibody. Consequently, our developed method is cost-effective for both the p53 capture and detection by compared with the conventional immunoassay. The biosensor developed by the above strategy was used to quantitatively detect p53, which yields a detection limit of 8 p.M. with the linear range of 50 p.M. to 2 nM. The sensitive for specific p53 detection was achieved due to the facile magnetic separation from the complex condition, and the reduced non-specific absorption effect by dextran. Moreover, the method is able to measure p53 from real cell lysate without extensive sample pretreatment/separation. The developed p53 biosensor has high sensitivity, good selectivity and reliable accuracy. It demonstrates great potential in clinical cancer diagnosis and early detection of cancer.

The joining capability of metal cellular structures fabricated using the additive manufacturing (selective laser melting (SLM)) method is investigated herein. The metal cellular structures are composed of sub-millimeter holes and internal pores. The direct joining of 3D-printed ABS-M30i thermoplastic parts to metal cellular structures by ultrasonic welding is demonstrated. The SLM-fabricated structures comprised of partially melted powders provide micro-scale roughness, which enhances the micro-mechanical interlocking between joining parts. A shear strength 17.7 MPa and normal tensile strength of 15.2 MPa were obtained, up to 55 and 48% of ABS-M30i ultimate tensile strength, respectively. Moreover, normal tensile plastic strength up to 86% of the shear strength was obtained.

This study aimed to study the impact of a combination of maternal and post-weaning high-fat diets and whether resveratrol was beneficial. Sprague-Dawley dams were fed either chow or a high-fat diet, before mating, during pregnancy, and into lactation. At weaning, their offspring were randomly fed chow or a high-fat diet. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal high-fat/postnatal chow diet), CH (maternal chow/postnatal high-fat diet), and HH (maternal/postnatal high-fat diet). A fifth group consisted of HH plus resveratrol. The 4 month-old offspring of HH group had higher body weight, higher levels of plasma triglycerides, leptin, angiotensin I and angiotensin II and abnormal intraperitoneal glucose tolerance test results, which fulfilled the features of metabolic syndrome. The dysregulation of the renin-angiotensin system was seen in multiple organs. Sirtuin 1 expression/abundance was reduced by a maternal/postnatal high-fat diet, in all the organs examined. Resveratrol ameliorated most of the features of metabolic syndrome and molecular alterations. The administration of a high-fat diet in both periods showed interactive metabolic effects in the plasma and many organs. Our results suggest that a maternal high-fat diet sensitizes offspring to the adverse effects of subsequent high-fat intake on multiple organs.

In the fight against pathogenic bacteria, traditional antibiotic therapy is challenged by low efficiency and drug resistance. These drawbacks motivate the development of synergistic antibacterial therapy, but there is a lack of efficient synergistic platforms. Herein, with methicillin-resistant Staphylococcus aureus (MRSA) as a pathogenic bacterial model, we explored the potential of black phosphorus (BP) as a synergistic therapeutic platform for drug resistant bacterial infection. Acting as a substrate, reductant and stabilizer, BP nanosheets were decorated with Ag nanoparticles (NP) through an in situ growth strategy. The photothermal effect of the BP nanosheets allows Ag@BP nanohybrids to rapidly disrupt a bacterial membrane under near infrared (NIR) light irradiation. Moreover, the slowly released Ag+ elevates oxidative stress and sustainably suppresses bacterial proliferation for a long time. The combination of these two aspects endows the Ag@BP nanohybrids with synergistically enhanced antibacterial performance. Different from traditional antibiotics, the antibacterial effects of the Ag@BP nanohybrids are independent of the bacterial structure, which bypasses the issue of drug resistance. The in vivo studies show that the Ag@BP nanohybrids efficiently decrease the MRSA bacterial burden in mice and minimize infection associated tissue lesions. Besides, the excellent biocompatibility of the Ag@BP nanohybrids guarantees their biosafety for future clinical applications. Accordingly, this work demonstrates the potential of the BP nanosheets in the synergistic antibacterial therapy against drug resistant bacteria, and paves the way for developing 2D semiconductor based synergistic antibacterial nanodrugs.

Background/Aims: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD+-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. Methods: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. Results: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-β1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-β1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-β1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-β1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-β1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. Conclusion: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

This cohort study aimed to investigate urinary cytokines expression to help identify a less invasive method of cytokine detection for Kawasaki disease (KD). Patients with confirmed KD were recruited. Patients with fever or urinary tract infection (UTI) were enrolled as control groups. Urinary samples were collected before and 3 days after intravenous immunoglobulin (IVIG) treatment. The levels of cytokines were detected by MILLPLEX® MAP human multiplex assay. All cytokines, i.e., epidermal growth factor (EGF), interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17A, IL-33, interferon-gamma-induced protein (IP)-10, macrophage inflammatory protein (MIP)-1β, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) except monocyte chemoattractant protein (MCP)-1 were significantly higher in the KD group, compared with the fever-control (FC) group, whereas the expressions of IFN-γ, IL-1β, IL-6, IL-8, IL-17A, IL-33, MCP-1, MIP-1β, and TNF-α were significantly lower in the urine of KD patients, as compared with the UTI group. The expressions of EGF, IFN-γ, IL-8, IL-13, and IL-17A were higher in the urine of KD patients than in the FC group, whereas the level of IL-1β was lower in KD than in the UTI group after age adjustment by logistic regression. Levels of IL-6, IL-8, IL-13, IP-10, and MCP-1 were significantly higher in the pre-IVIG urine of KD patients than in the post-IVIG treatment group. Additionally, urine IL-4 and blood C-reactive protein were higher in the KD group with coronary artery lesion (CAL) than in the non-CAL group. Results of this study provide a new view of urinary cytokine expression in the disease progress of KD, which may help clinicians to predict and prevent morbidity early and non-invasively.

AKR1C3 is overexpressed at both levels of protein and RNA in many types of cancer, particularly in liver, gastric, renal, CRPC and non-small cell lung cancer. High AKR1C3 expression is directly related to treatment resistance and poor prognosis. AST-3424/OBI-3424 (denoted by 3424) is a novel prodrug activated by AKR1C3. Currently 3424 is being studied in phase I clinical trials for the treatment of solid and hematologic cancers. Here we characterize 3424 on its specificity against AKR1C3 in biochemical and cell-based assays. In addition, its anti-tumor activity as a single agent or in combination therapy in a broad panel of CDX and PDX models was also investigated. AKR1C3-dependent activation of prodrug 3424 was evident by monitoring the decrease of 3424 and generation of the active form, 2660, based on LC/MS-MS analysis. Kinetic analysis indicated that AKR1C3 exhibited higher catalytic efficiency towards 3424 compared to the physiological substrates. Cytotoxicity of 3424 was found to be dependent on the level of AKR1C3 expression in a wide range of human cancer cell lines. There was a strong correlation between 3424 cytotoxic potency and AKR1C3 expression at both protein and RNA levels across all the cell lines examined. Cytotoxicity of 3424, its enantiomer and racemic mixture were also greatly inhibited by the AKR1C3-specific inhibitor 3021. The racemic mixture induced DNA cross-linking in a concentration dependent manner. Tumor growth inhibition of 3424 was shown to be better than or comparable to the standard of care chemotherapy at clinically achievable doses as a single agent in various CDX models with high expression of AKR1C3 at both levels of protein and RNA, including gastric SNU-16, kidney A498, and castration-resistant prostate VCaP, liver HepG2 and lung H460 cancers. The excellent anti-tumor efficacy of 3424 was further demonstrated in PDX models that have high level of AKR1C3 expression (pancreatic PA1280, gastric GA6201, Lung cancer LU2505) but not in model with low level of AKR1C3 expression (lung cancer LU2057). A significant correlation was found between AKR1C3 expression level and 3424 anti-tumor activity in two lung LU2505 and LU2057 PDX xenograft models confirming that 3424 in vivo activity is AKR1C3-dependent, which is consistent with its AKR1C3-dependent cytotoxicity in vitro. In the combination therapy, we have showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models of VCaP CRPC, SNU-16 gastric, and A498 renal cell carcinoma. In conclusion, the results described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancer and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424. Citation Format: Fanying Meng, Wan-Fen Li, Donald Jung, Chun-Chung Wang, Tianyang Qi, Chi-Sheng Shia, Ren-Yu Hsu, Yin-Cheng Hsieh, Jianxin Duan. Selective and broad anti-tumor activity of AKR1C3-activated prodrug AST-3424/OBI-3424 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1220.

Stage-specific embryonic antigen-4 (SSEA-4) ceramide, a globo-series hexasaccharide glycosphingolipid, has been reported to be a tumor-associated antigen. Here, we present a novel antibody-drug conjugate (ADC) targeting SSEA-4 to evaluate its potential as a therapeutic agent for cancer treatment. OBI-998 is an ADC comprising the humanized anti-SSEA-4 antibody (OBI-898) that is conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE) through maleimide and PEGylated cleavable linkers. We demonstrated the specificity of the naked antibody to SSEA-4 by screening against a panel of 21 related carbohydrate antigens using ELISA. OBI-998 displayed potent cytotoxic activity against cells (SKOV3) with a high level of SSEA-4 expression at sub-nanomolar potency but no effect on the viability of cells (SKBR3) with negligible SSEA-4 expression. The bystander killing effect of OBI-998 was shown by the transferring of conditioned medium from SKOV3 cells treated with 1 or 5 nM of OBI-998 to SKBR3 cells. Furthermore, significant bystander effects were observed by co-culturing high (NCI-N87) and low (PANC-1/GFP) SSEA-4-expressing cell lines at different ratios in the presence of 5 or 10 nM of OBI-998. OBI-998 was found to be rapidly internalized into cancer cells within 5 minutes upon binding to its target on the cell surface by confocal microscopy. OBI-998 showed significant anti-tumor efficacy in multiple cancer cell–derived xenograft models at doses of 1, 3, and 10 mg/kg in a dose-dependent manner. More importantly, OBI-998 at a dose of 10 mg/kg showed complete tumor regression in an EGFR-triple mutation non–small cell lung cancer xenograft model, which is resistant to the current last-line tyrosine kinase inhibitor, osimertinib. Pharmacokinetic analysis of OBI-998 revealed that total antibody and the conjugated antibody exhibited similar pharmacokinetic profiles, suggesting OBI-998 is highly stable in vivo. The biodistribution study in HCC1428 tumor-bearing mice indicated that MMAE accumulated in the tumor site at a higher level compared with other blood-rich organs. In addition, the MMAE levels in tumors reached peak level at 24 hours post-treatment, which was much higher than the maximum levels in other organs, and the level was sustained for 168 hours with tumor-to-muscle ratio of 329. OBI-998 is a novel ADC targeting SSEA-4 that possesses desired properties such as high target specificity, rapid internalization, potent cytotoxicity, and significant bystander effects. Furthermore, OBI-998 showed a high level of deposition and a persistent presence of MMAE in tumors and significant anti-tumor efficacy in a variety of animal models. Taken together, these results support the further development of OBI-998 as a therapeutic agent for SSEA-4-targeting cancer therapy. Citation Format: I-Ju Chen, Chun-Chung Wang, Chi-Sheng Shia, Chung-Chen Su, Chi-Huan Lu, Hui-Wen Chang, Ping-Tzu Chiu, Yueh-Chin Wu, Ming-Tain Lai, Wei-Chien Tang, Hsin-Yi Tung, Ren-Yu Hsu. Preclinical characterization of a novel SSEA-4-targeting antibody drug conjugate, OBI-998 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 955.

// Shih-Wen Li 1, 2 , Hong-Ren Yu 1 , Jiunn-Ming Sheen 1 , Mao-Meng Tiao 1 , You-Lin Tain 1 , I-Chun Lin 1 , Yu-Ju Lin 3 , Kow-Aung Chang 4 , Ching-Chou Tsai 5 and Li-Tung Huang 1, 6 1 Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 3 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan 4 Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan 6 Department of Traditional Medicine, Chang Gung University, Linkow, Taiwan Correspondence to: Li-Tung Huang, email: litung.huang@gmail.com Keywords: maternal high-fat diet/obesity; spatial; resveratrol; postnatal high-fat diet; hippocampus Received: August 16, 2017 Accepted: November 17, 2017 Published: December 06, 2017 ABSTRACT We tested the hypothesis that high-fat diet consumption during pregnancy, lactation, and/or post weaning, altered the expression of molecular mediators involved in hippocampal synaptic efficacy and impaired spatial learning and memory in adulthood. The beneficial effect of resveratrol was assessed. Dams were fed a rat chow diet or a high-fat diet before mating, during pregnancy, and throughout lactation. Offspring were weaned onto either a rat chow or a high-fat diet. Four experimental groups were generated, namely CC, HC, CH, and HH (maternal chow diet or high-fat diet; postnatal chow diet or high-fat diet). A fifth group fed with HH plus resveratrol (HHR) was generated. Morris water maze test was used to evaluate spatial learning and memory. Blood pressure and IPGTT was measured to assess insulin resistance. Dorsal hippocampal expression of certain biochemical molecules, including sirtuin 1, ERK, PPARγ, adiponectin, and BDNF were measured. Rats in HH group showed impaired spatial memory, which was partly restored by the administration of resveratrol. Rats in HH group also showed impaired glucose tolerance and increased blood pressure, all of which was rescued by resveratrol administration. Additionally, SIRT1, phospho-ERK1/2, and phospho-PPARγ, adiponectin and BDNF were all dysregulated in rats placed in HH group; administration of resveratrol restored the expression and regulation of these molecules. Overall, our results suggest that maternal high-fat diet during pregnancy and/or lactation sensitizes the offspring to the adverse effects of a subsequent high-fat diet on hippocampal function; however, administration of resveratrol is demonstrated to be beneficial in rescuing these effects.

Polylactic acid (PLA) nonwoven fabrics are treated with atmospheric dielectric barrier discharge (DBD) plasma to improve surface wettability. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) show that micro- to nano-scale textures appear on the treated PLA surfaces dependent on the treatment time. X-ray photoelectron spectroscopy (XPS) analysis reveals that the DBD plasma treatments result in decreased carbon contents and increased oxygen contents as well as slightly increased nitrogen contents. The water contact angle decreases sharply with the increase of the DBD plasma treatment time. The super hydrophilic PLA surfaces (the water contact angle reached 0°) are obtained when the treatment time is longer than 90 s. Ninety days after the DBD plasma treatment, the XPS analysis shows that C O/C N and C O/O C O percentages decline for all treatment groups. However, the water contact angle is kept constant at 0° for the groups treated above 90 s, which could be due to the oxidized nano-structured layer on the DBD plasma treated PLA surfaces.

Two new (1–2) and one known (3) benzophenone derivatives, along with five known ambuic acid analogues (4–8) were isolated from the solid cultures of a Pestalotiopsis sp. Compound 2 represented both enantiomeric and atropisomeric isomers, and the absolute configurations of enantiomers [(−)-2 and (+)-2] were determined by electronic circular dichroism (ECD) calculations. All the isolates were evaluated for their antimicrobial and cytotoxic activities. Chlorinated compounds 2 and 3 showed potent antimicrobial activities against four pathogenic bacteria, and compound 3 also displayed strong antifungal activity against Candida glabrata (ATCC 90030) with an MIC50 value of 2.6 ± 0.1 μg/mL. Compound 1 exhibited moderate cytotoxicity against U2OS and MCF-7 with IC50 values of 11.6 and 16.8 μM, respectively.

To obtain new modified clays with excellent algae removal efficiency, three gemini surfactants including ethylene bis (dodecyl dimethyl ammonium chloride), ethylene bis (octadecyl dimethyl ammonium chloride) and ethylene bis (dodecyl dimethyl ammonium bromide) (EDAB), and a poly quaternary ammonium salt, poly dimethyl diallyl ammonium chloride, were screened with Chattonella marina. The four chemicals all exhibited high removal efficiencies against C. marina, with EDAB achieving the highest. A series of organ-clays with different ratios of EDAB were prepared, and the associated removal efficiencies were evaluated. The removal efficiencies of the organ-clays were improved by the EDAB intercalation and the organ-clay with 15% EDAB had the highest removal efficiency. The LC50 of EDAB intercalated clay for zebrafish and shrimp was much higher than the values of intercalated clay required to obtain a desirable removal efficiency of algae. Taken together, EDAB intercalated clay might be a potential alternative to control harmful algal blooms (HABs).

Maternal high-fat (HF) diet is believed to induce oxidative stress and activate nutrient-sensing signals, which increase the risk of adult offspring to develop hypertension. We investigated whether resveratrol prevents the combined maternal plus postweaning HF-diets-induced hypertension in adult male offspring, with a focus on the kidney. Female Sprague–Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for 5 weeks before mating and during gestation and lactation. The male offspring were placed on either the ND or HF diet from weaning to 4 months of age, resulting in four experimental groups (maternal diet/postweaning diet; n =8–10/group): ND/ND, ND/HF, HF/ND and HF/HF. Another group of HF/HF rats ( n =10) was treated with 0.5% resveratrol in drinking water between 2 and 4 months of age (HF/HF+R). Rats were killed at 4 months of age. We found that HF/HF-induced hypertension in adult offspring was prevented by resveratrol. Resveratrol mediated its protective effect on HF/HF-induced hypertension in the kidneys of male offspring by diminishing oxidative stress; reducing renal asymmetric dimethylarginine levels; mediating the renin–angiotensin system (RAS) in favor of vasodilatation; restoring nutrient-sensing pathways via increased levels of silent information regulator transcript 1 (SIRT1), AMP-activated protein kinase 2α and peroxisome proliferator-activated receptor gamma coactivator 1-α; and inducing autophagy. Our data implicated an association between oxidative stress, RAS, nitric oxide, and nutrient-sensing signals in HF/HF-induced hypertension. Resveratrol, acting as an antioxidant as well as a SIRT1 activator, might be a therapeutic approach for hypertension.

The objective of this work is to establish a new pore-scale (m–μm) model for estimating the dissociation rate of methane hydrate (MH) synthesized in laboratory-scale sediment samples. Finite volume method (FVM) with unstructured mesh were constructed in a representative face-centered cubic unit. The surface model of MH reported by Sean et al. (2007) has been employed. In the bulk flow, concentration of methane in water flow was analyzed by computational fluid dynamics (CFD) method. However, only water flow and solid MH are simulated without considering ice or gas phase. In this study, tentative cases with porosity 0.74, 0.66, and 0.49 is individually considered as representative cubic unit of MH array. The initial temperature, 253.15 (K) of MH pellets inside the cubic unit dissociated due to the driving force of fugacity variation, ex. 0.56 and 0.54 (MPa) while warm water of 282.15 and 276.15 (K) flow in. In the calculation, periodic conditions are imposed at surfaces of inlet/right/front sides updated every time step. The flux of methane at the surface are all regarded as being dissolved into the water in this high pressure state, and compared to Kim et al. (1987)’s correlation at Reynolds no. of about 50. Results of dissociation flux in cases 5 and 6 with porosity 0.49 show good agreements with Kim’s correlation. However, as the porosity increases, flux increases due to the fast transport in bulk flow such as cases 1–4 in this study. If the transport process in bulk flow is faster than dissociation rate, then the surface flux becomes saturated as Reynolds no. greater than 100 in this work.

Blood testing for endogenous small metabolites to determine physiological and biochemical states is routine for laboratory analysis. Here we demonstrate that by combining the commercial direct analysis in real time (DART) ion source with an ion trap mass spectrometer, native cholesterol in its free alcohol form is readily detected from a few hundred nanoliters of human serum loaded onto chromatography paper. Deuterium-labeled cholesterol was used as the internal standard to obtain the absolute quantity of the endogenous cholesterol. The amount of the cholesterol measured by this paper-loaded DART mass spectrometry (pDART-MS) is statistically comparable with that obtained by using commercially available fluorometric-enzymatic assay and liquid chromatography/mass spectrometry. Furthermore, sera from 21 participants at three different time points in an ultramarathon were collected to obtain their cholesterol levels. The test requires only very minimal sample preparation, and the concentrations of cholesterol in each sample were acquired within a minute.

The combination treatment of dielectric barrier discharge (DBD) plasma and chitosan coatings was performed on ultrahigh molecular weight polyethylene (UHMWPE) fibers in order to improve the wettability, dyeability and adhesion properties. The properties of UHMWPE fibers coated with chitosan, after being pretreated by DBD plasma, were evaluated through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The interfacial shear strength (IFSS) between the fiber and the epoxy resin was determined using the single fiber pull-out test technique. The modified UHMWPE fibers were dyed with reactive dyes after the combined treatment. Surface wettability and dyeability were investigated by water contact angle and K/S measurement, respectively. SEM images confirmed that the chitosan was induced onto the surfaces of the UHMWPE fibers after the combined treatment. The XPS analysis showed that the oxygen and nitrogen contents of the UHMWPE fiber surfaces after the combined treatment were higher than that of the fiber modified by chitosan without DBD plasma pretreatment. Meanwhile, the UHMWPE fibers treated with combination of DBD plasma and chitosan treatment had better wettability, dyeability and adhesion property than those of the non-plasma pretreated surfaces, indicating that DBD plasma pretreatment facilitated the deposition of chitosan onto the UHMWPE surfaces.

Background Intensifying weed resistance has challenged the use of existing acetohydroxyacid synthase (AHAS)-inhibiting herbicides. Hence, there is currently an urgent requirement for the discovery of a new AHAS inhibitor to effectively control AHAS herbicide-resistant weed species produced by target mutation. Results To combat weed resistance caused by AHAS with P197L mutation, we built a structure library consisting of pyrimidinyl-salicylic acid derivatives. Using the pharmacophore-linked fragment virtual screening (PFVS) approach, hit compound 8 bearing 6-phenoxymethyl substituent was identified as a potential AHAS inhibitor with antiresistance effect. Subsequently, derivatives of compound 8 were synthesized and evaluated for their inhibitory activities. The study of the enzyme-based structure-activity relationship and structure-resistance relationship studies led to the discovery of a qualified candidate, 28. This compound not only significantly inhibited the activity of wild-type Arabidopsis thaliana (At) AHAS and P197L mutant, but also exhibited good antiresistance properties (RF = 0.79). Notably, compared with bispyribac at 37.5-150 g of active ingredient per hectare (g a.i. ha-1 ), compound 27 exhibited higher growth inhibition against both sensitive and resistant Descurainia sophia, CONCLUSION: The title compounds have great potential to be developed as new leads to effectively control herbicide-resistant weeds comprising AHAS with P197L mutation. Also, our study provided a positive case for discovering novel, potent and antiresistance inhibitors using a fragment-based drug design approach.

Background: The leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) is considered a cancer stem cell marker, and is often overexpressed in tumors. The interaction between Lgr5 and the immune-related tumor microenvironment is not completely understood. The aim of this study was to examine the role of Lgr5 in the microenvironment of gastric cancer (GC), and to explore possible immunological mechanisms influencing Lgr5 expression that are governed by regulatory T cells. Methods: Lgr5 expression was examined in 180 GC tumors by immunohistochemistry, and in 80 pairs of GC tumors for analysis of Th1/Th2 cytokines by ELISA. In addition, SGC7901 cells were co-cultured with patient-derived Tregs, varying concentrations of TGF-β1, TGF-β1 neutralizing antibody, or TGF-β receptor inhibitor SB431542, and Lgr5 and β-catenin expression were examined by qRT-PCR and western blot. Results: In this study, an immunosuppressive microenvironment was associated with high Lgr5 expression in GC. Furthermore, Lgr5 expression was up-regulated in GC cells co-cultured with Tregs or treated with exogenous TGF-β1. This up-regulation was partially inhibited by the TGF-β1 neutralizing antibody, or TGF-β1 receptor antagonist SB431542. β-catenin was up-regulated with high Lgr5 expression induced by exogenous TGF-β1, and this up-regulation was inhibited by SB431542. An increased number of Tregs and high Lgr5 expression in GC tissues were significantly associated with low overall survival. Conclusion: Tregs promoted increased Lgr5 expression in GC cells via TGF-β1 and TGF-β1 signaling pathway, which may involve activation of the Wnt signaling pathway. High Lgr5 expression via TGF-β confer poor prognosis in gastric cancer.

Increased plasma concentration of asymmetric dimethylarginine (ADMA) can be encountered in chronic inflammatory disease, liver damage, renal failure, and multiple organ failure. In addition, an association between circulating ADMA and all-cause mortality has been reported. Male Sprague-Dawley rats, postnatal day (PND) 17 ± 1, received continuous ADMA infusion via an intraperitoneal pump. Spatial performance, as well as plasma and dorsal hippocampus ADMA and brain-derived neurotrophic factor (BDNF) concentration, were examined and the effect of melatonin was tested. We found that a 4-week continuous ADMA infusion in young rats caused spatial deficit. Furthermore, increased ADMA concentration and decreased BDNF expression were found in the plasma and dorsal hippocampus. Melatonin protected against these effects, alleviating spatial deficit and reducing the changes in plasma and dorsal hippocampus ADMA and BDNF concentration.

Background The specific disease, intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-complication. However, there are no indications for ICP in the domestic licenced drugs for protecting the liver and reducing bile acid levels, which are often based on evidence-based medicine or evidence-based pharmacy to select drugs that have been used during pregnancy and have no teratogenic evidence. Methods By analyzing the drug use (Reduced glutathione for injection, Inosine injection and Ursodeoxycholic acid tablets) and the allergic reactions in the clinical practice in a rare patient with hepatic disorders in third trimester of pregnancy, in order to remind clinicians that in the course of using hepatoprotective and bile acid-lowering drugs, their current clinical practice was not always safety. Especially when using two or more hepatoprotective drugs, should pay more attention to whether it will aggravate the risk of adverse reactions or even allergic reactions. Results Based on the literature reports and the corresponding drug instructions, it is concluded that all three drugs might cause allergic reactions, but there are few reports of allergic reactions caused by ursodeoxycholic acid tablets. So far, there have been no reports of two allergic reactions for three drugs in the same patient in a short period. In this case, we judged that the first allergic reaction was caused by reduced glutathione for injection, and the second allergic reaction was caused by inosine injection, but the combination of ursodeoxycholic acid tablets may aggravate the allergic reaction. Conclusions 1. Reduced glutathione for injection may lead to severe allergic reactions in women in the third trimester of pregnancy. 2. Ursodeoxycholic acid tablets may aggravate the risk of allergic reactions for inosine injection when combined with both drugs is used to protect liver and reduce bile acid levels in women in the third trimester of pregnancy.

Scope Prenatal high-fat (HF) and postnatal HF diet are both associated with obesity and metabolic disturbances in adults. Leptin resistance induced by obesity limits its biological effects. The anti-obesity mechanism of resveratrol in visceral adiposity is investigated here. Methods and results During mating and lactation, Sprague-Dawley dams are fed either control or a HF diet. Subsequently, the offspring are fed chow or an HF diet. A fifth group that received maternal/postnatal HF diet and resveratrol after weaning (HHR) is used to study the effects of resveratrol treatment. Resveratrol treatment alleviates adiposity programed by maternal and postnatal HF diet by decreasing feed intake or inducing metabolic changes. Resveratrol treatment is also found to ameliorate the decrease in SIRT1 abundance observed in retroperitoneal adipose tissue, programed by maternal and postnatal HF diet. Moreover, resveratrol therapy decreases plasma leptin level and increases leptin receptor expression in retroperitoneal adipose tissue through DNA methylation modification. Conclusion These results suggest that resveratrol can alleviate peripheral leptin resistance programed by the combined effect of prenatal and postnatal HF diet through epigenetic regulation of genes coding leptin and its receptor. It provides insights into a novel mechanism explaining the beneficial effects of resveratrol in obesity management.

In order to improve the application range of lignin phenolic resin, lignin thermoplastic phenolic resin was prepared by controlling the molar ratio (formaldehyde: phenol) with liquefied lignin, phenol and formaldehyde as raw materials, and thermoplastic phenolic fiber was obtained by melt spinning. The effects of different curing bath acid proportion (40%, 50%, 60%) on the mechanical property, thermal property and morphology of the fiber were investigated, and the curing behavior of lignin phenolic fiber was studied. The structure and properties of the resin and fiber were characterized by FT-IR, NMR, GPC, TG, DSC, XRD, SEM and fiber strength testing. The results showed that when the molar ratio was 0.7:1, the resin had the best performance, the O/P value was 1.75, Mw was 8298, and PDI was 2.92. After curing, the fiber continued cross-linking reaction, and the diameter of the cured fiber was thicker than that of the original fiber. The most suitable curing process for the original fiber was that formaldehyde and hydrochloric acid were prepared into curing bath according to the mass ratio of 1:1, the heating rate was 20 ℃ h−1, the curing termination temperature was 170 ℃. The tensile strength of the fibers reached 176.64 MPa and the elongation at break was 1.48%, and finally the carbon yield at 800 ℃ was 37.2%.

BACKGOUND Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application of AHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS. RESULTS Pyrimidinyl-Salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant. In current work, a series of novel 2-benzoyloxy- 6-pyrimidinyl salicylic acid derivatives were designed through fragment-based drug discovery (FBDD). Fortunately, the newly synthesized compounds showed a good inhibitory activity against both wild-type and P197L mutant. Some compounds not only had a lower resistance factor value, but also showed an excellent inhibitory activity against wild type AHAS and P197L mutant. Furthermore greenhouse experiments showed compound 11 m displayed almost 100% inhibition against both wild-type and high-resistant Descurainia sophia at the dosage of 150 g.ai/ha. CONCLUSION The present work indicated that the 2-benzoyloxy- 6-pyrimidinyl salicylic acid motif was well worth further optimization. And compound 11 m can be used as a potential anti-resistant AHAS herbicide which requires further research.

We develop a new lysosome-targeting AIE fluorescent probe tetraphenylethene-morpholine (TPE-MPL), by incorporating a typical lysosome-targeting moiety of morpholine into a stable tetraphenylethene skeleton. Due to both the AIE and antenna effects, TPE-MPL possesses superior photostability, appreciable tolerance to microenvironment change and high lysosome targeting ability. Our findings confirm that TPE-MPL is a well-suited imaging agent for targeting lysosome and tracking dynamic movement of lysosome. Moreover, due to its synthetic accessibility, TPE-MPL could be further modified as a dual-functional probe for lysosome, thereby gain further insight into the role of lysosome in biomedical applications.

Serum creatinine (Scr), which is a conventional indicator of contrast-induced nephropathy (CIN), is unable to reflect the damage of kidney promptly. The present study aimed to investigate the value of neutrophil gelatinase-associated lipocalin (NGAL) in kidney and serum of CIN rats to observe whether NGAL can be used as a superior indicator of CIN. Furthermore, N-acetylcysteine (NAC) was used to assess its effect on CIN. A total of 120 adult male Sprague Dawley rats were randomly divided into four groups (n=30/group): CIN rats (CIN), normal rats treated with NAC (NAC), CIN rats treated with NAC (NAC+CIN) and the control group (CON). Serum Scr and NGAL values were measured at 2, 12, 24, 48 and 72 h following the procedure. Immunohistochemistry and western blot analysis were used to detect NGAL within the kidney tissue. Hematoxylin and eosin staining were used to access the renal injury score. Oxidative stress within the kidney was analyzed via malondialdehyde (MDA) and superoxide dismutase (SOD). The level of NGAL in the serum and tissue of the CIN group increased significantly 2 h after the procedure (P

The adsorption of various combinations of three polar molecules (NH 3 , H 2 O, and HF) on Si/Ge(100) surface is studied by first-principles calculations. On a given pre-adsorbed substrate, the H-bonding and dative bonding always show a synergistic effect, together with the electrostatic attraction, dominating the adsorption and dissociation of polar molecules on Si/Ge(100). Both H 2 O and HF are found to be energetically favored to cluster with the pre-adsorbed H 2 O molecule on Si/Ge(100) surface. Catalyzed by H 2 O, the dissociation barriers of H 2 O on Ge(100) decrease from ~ 0.7 to ~ 0.4 eV, in comparison with the nearly an order of magnitude reduction on Si(100). Furthermore, H 2 O molecule dissociates spontaneously on Si(100) and the barriers are lowered to ~ 0.2 eV on Ge(100) when catalyzed by HF, providing an efficient approach for dissociation of H 2 O on Si(100) and Ge(100) surfaces.