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Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of diseases and challenges remain for the current medications. Herein, we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways. A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate (EGCG) through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety. BH-EGCG molecules readily form stable nanoparticles in aqueous medium, which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites. Additionally, an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&NAC@MM to further improve the anti-inflammatory efficacy. Benefiting from the inflammation-homing effect of the macrophage membrane, the nanosystem delivers payloads (diagnostic probe and therapeutic drugs) to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS, thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models, including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation. This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases., Graphical abstract Image 1, Highlights • A multifunctional nanosystem has been developed for targeting, imaging and treating immune-mediated inflammatory diseases. • Once activated the nanosystem generates fluorescent/optoacoustic signals for diagnosis and evaluating therapeutic efficacy. • The released drugs EGCG and NAC in inflammation site treat the diseases via inhibiting NF-κB/NLRP3 pathways.

A highly active and stable Ni-based catalyst is the focal point for research on dry reforming of methane (DRM). Here, NixGay/La2O3-LDO catalysts composed of highly dispersed NixGay and La2O3 nanoparticles supported by the MgO/Al2O3 layered double oxide (LDO) nanosheets were synthesized by chemical methods. According to transmission electron microscopy (TEM), energy-dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), CO2-TPD, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and thermal gravitational analysis (TGA), a synergistic reaction mechanism was proposed to explain the superior performance of the Ni0.8Ga0.2/La2O3-LDO catalyst. The NixGay alloy catalyst provides an effective way to balance the speed of CH4 cracking and CO2 disassociation, and the La2O3 promoter enriched the CO2 and ensured the generation of active O in time. They worked together to inhibit carbon accumulation and significantly improve the catalyst's activity and stability.

Introduction Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swept rapidly throughout the world. So far, no therapeutics have yet proven to be effective. Ribavirin was recommended for the treatment of COVID-19 in China because of its in vitro activity. However, evidence supporting its clinical use with good efficacy is still lacking. Methods A total of 208 confirmed severe COVID-19 patients who were hospitalized in Wuhan Union West Campus between 1 February 2020 and 10 March 2020 were enrolled in the retrospective study. Patients were divided into two groups based on the use of ribavirin. The primary endpoint was the time to clinical improvement. The secondary endpoints included mortality, survival time, time to throat swab SARS-CoV-2 nucleic acid negative conversion, and the length of hospital stay. Results 68 patients were treated with ribavirin while 140 not. There were no significant between-group differences in demographic characteristics, baseline laboratory test results, treatment, and distribution of ordinal scale scores at enrollment, except for coexisting diseases especially cancer (ribavirin group vs no ribavirin group, P = 0.01). Treatment with ribavirin was not associated with a difference in the time to clinical improvement (P = 0.48, HR = 0.88, 95% CI = 0.63–1.25). There were also no significant differences between-group in SARS-CoV-2 nucleic acid negative conversion, mortality, survival time, and the length of hospital stay. Conclusions In hospitalized adult patients with severe COVID-19, no significant benefit was observed with ribavirin treatment.

Eurysoloids A (1) and B (2), two novel diastereomeric sesterterpenoids possessing a pentacyclic 5/6/5/10/5 framework with an unusual macrocyclic ether system, were isolated from Eurysolen gracilis Prain. Their structures were unambiguously determined by spectroscopic, single-crystal X-ray diffraction and DP4+ analyses. A plausible biosynthetic pathway for compounds 1 and 2 was proposed. Both compounds exhibited immunosuppressive activity via inhibiting the production of cytokine IFN-γ of T cells, and compound 2 inhibited adipogenesis in 3T3-L1 adipocytes.

Type II diabetes is a prevalent disease; if left untreated, it could cause serious complications including liver and kidney damages. Hence, early diagnosis for these damages and effective treatment of diabetes are of high importance. Herein, a fluorophore-dapagliflozin dyad (DX-B-DA) has been developed as a theranostic system that can be triggered by intrahepatic/intrarenal reactive oxygen species (ROS) to concomitantly release a near-infrared (NIR) fluorescent dye (DX) and a SGLT2 inhibitor dapagliflozin (DA). In this dyad (DX-B-DA), the NIR fluorophore (DX) and the drug DA were covalently linked through a boronate ester bond which serves as the fluorescence quencher as well as the ROS-responsive moiety that can be cleaved by pathological levels of ROS in diabetics. The in vitro experiments indicate that, in the absence of hydrogen peroxide, the dyad is weakly emissive and keeps its drug moiety in an inactive state, while upon responding to hydrogen peroxide, the dyad simultaneously releases the NIR dye and the drug DA, suggesting that it can serve as an activatable probe for detecting and imaging diabetic liver/kidney damages as well as a prodrug for diabetes treatment upon being triggered by ROS. The dyad was then injected in mouse model of type II diabetes, and it is found that the dyad can not only offer visualized diagnosis for diabetes-induced liver/kidney damages but also exhibit high efficacy in treating type II diabetes and consequently ameliorating diabetic liver/kidney damages.

As a synthetic functional analog of salicylic acid, 2,6-dichloroisonicotinic acid (INA) is effective in inducing the host disease resistance of a plant against a pathogen. The effects of INA on controlling postharvest blue and green molds and anthracnose decay and defense-related enzymes on citrus fruits were investigated, and the ascorbic acid of naturally infected citrus flavedo was also measured. Results showed that 1.0 mmol L−1 INA treatments significantly reduced blue and green molds and anthracnose decay development on both wound-inoculated fruit and naturally-infected fruit compared with the control fruit. The treatment effectively enhanced the β-1,3-glucanase (GLU), chitinase (CHI), phenylalanine ammonia-lyase (PAL) and peroxidase (POD) activities and the polyphenol oxidase (PPO) in flavedo. The results presented here suggest that INA might be used as a chemical fungicide substitution to control postharvest diseases in citrus fruits.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease associated with progressive disability, systemic complications, and poor prognosis. The improved understanding of the roles of immune signaling pathway inhibitors has shed light on designing new and more effective approaches for RA treatment. In this work, an inflammation-responsive and molecularly targeted drug system has been developed for RA therapy. The drug carrier was synthesized by covalently grafting hydrophobic cholesterol (Chol) molecules onto a hydrophilic chondroitin sulfate (CS) chain via the inflammation-responsive diselenide bonds (SeSe). The resultant amphiphilic polymer CSSeSeChol readily forms nanoparticles (NPs) and encapsulates two kinase inhibitors tofacitinib and SP600125 in aqueous media. Upon administration into the RA mouse model, the nanodrug accumulates in RA lesions and releases the inhibitors for regulating the JAK-STAT and JNK pathways. As a result, the nanodrug exhibits satisfactory efficacy in RA treatment by suppressing the expression of relevant pro-inflammatory cytokines, blocking the activation of osteoclasts and providing protection for cartilage and joints.

Summary Endogenous nitric oxide is important for living beings; hence, accurate and non-invasive detection of nitric oxide (NO) in situ is of significance. Benzothiadiazole-core chromophores are important near-infrared II (NIR-II) dyes, but such limitations as fluorescence quenching in aqueous media and non-activatable response constitute major barriers for biological applications. To address these issues, here we report an activatable nanoprobe, BNDA@HβCD, with aggregation-induced emission for detecting the biomarker NO. The molecular probe BNDA and 2-hydroxypropyl-β-cyclodextrin (HβCD) form the amphiphilic host-guest complex BNDA-HβCD, which readily forms nanoaggregates in aqueous media and thereby affords the nanoprobe BNDA@HβCD. NO reacts with the probe and generates the activated probe, which displays strong NIR-II fluorescence emission and optoacoustic signals. BNDA@HβCD can detect liver injury and monitor therapeutic outcome in a mouse model by detecting hepatic NO; it can also image NO in soybean sprouts. The results indicate that BNDA@HβCD is a robust tool for detecting NO in both animals and plants.

Background: Our previous study indicates that Brucea javanica oil (BJO) is beneficial for treatment of ulcerative colitis (UC), and that quassinoids in particular brusatol are bioactive components. However, it is still uncertain whether or not other components in BJO, such as oleic acid and fatty acids, have anti-UC effect.Purpose: The present study aimed to compare the anti-UC effects between brusatol-enriched BJO (BE-BJO) and brusatol-free BJO (BF-BJO), and to explore the effects and mechanisms of BE-BJO on colon inflammation and intestinal epithelial barrier function.Methods: Balb/C mice received 3% (wt/vol) DSS for one weeks to establish the UC model. Different doses of BE-BJO, BF-BJO or BJO were treated. Body weight and colon length were measured. Disease activity index (DAI) and histological analysis were evaluated. The levels of pro-inflammatory cytokines in the colon tissues were measured by enzyme linked immunosorbent assay (ELISA). The expressions of tight junction proteins were tested to investigate the intestinal epithelial barrier function. The effects of BE-BJO on NF-κB and RhoA/ROCK pathways were studied.Results: BE-BJO alleviated DSS-induced loss of body weight, increase of DAI and shortening of colon, whereas BF-BJO did not have these protective effects. BE-BJO treatment improved the morphology of colon tissue, inhibited the production and release of pro-inflammatory cytokines including TNF-α、 IFN-γ、 IL-6 and IL-1β in the colon tissue, as well as reversed the decreased expressions of ZO-1, Occludin, Claudin-1and E-cadherin induced by DSS, but augmented Claudin-2 expression. Mechanistically, BE-BJO repressed phosphorylation of NF-κB subunit p65, suppressed RhoA activation, downregulated ROCK, and prevented phosphorylation of myosin light chain (MLC) in DSS-treated mice.Conclusions: This work demonstrated that BE-BJO could ameliorate DSS-induced UC by preventing colon inflammation and enhancing intestinal epithelial barrier function, probably via suppression of NF-κB and RhoA/ROCK signaling pathways. These findings confirm that quassinoids are active compounds from BJO and suggest the therapeutic potential of quassinoids and BE-BJO in the treatment of UC.

Background and objective: soy protein and soy isoflavones have been suggested to be associated with improved cardiovascular risk factors (e.g., lipid profiles and uric acid (UA)), but few studies have been conducted among women with impaired glucose regulation (IGR). This study is aimed to evaluate the effect of isolated daidzein and genistein on lipid profiles, high sensitive C-reactive protein (hs-CRP), and uric acid (UA) among Chinese women with IGR. Methods and results: this randomized, double-blind, and placebo-controlled trial was conducted in 165 Chinese women aged 30–70 years with IGR. Participants were randomly assigned to one of the three groups: 0 mg of daidzein and genistein with 10 g soy protein (placebo group), 50 mg of daidzein with 10 g soy protein (daidzein group), or 50 mg of genistein with 10 g soy protein (genistein group) supplementation for 24 weeks. Fasting serum total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), lipoprotein a (LP (a)), hs-CRP, and UA were assessed at baseline, 12, and 24 weeks after intervention. The results showed no significant differences in the changes (%) of TC, TG, HDL-C, LDL-C, LP (a), hs-CRP, and UA between the three treatment groups at weeks 12 or 24 (all P > 0.05). Conclusion: neither isolated daidzein nor genistein had a significant effect on cardiovascular health in Chinese women with IGR.

Odorant binding proteins (OBPs) play a key role in chemoreception in insects. In an earlier study, we identified CmedOBP14 from the rice leaf folder, Cnaphalocrocis medinalis, with potential physiological functions in olfaction. Here, we performed a competitive binding assay under different pH conditions as well as knockdown via RNA interference to determine the specific role of CmedOBP14 in C. medinalis. CmedOBP14 displayed broad binding affinities to many host-related compounds, with higher affinities at pH 7.4 compared with pH 5.0. After treatment with CmedOBP14-dsRNA, the transcript level of OBP14 was significantly decreased at 72 h compared with controls, and the electroantennogram response evoked by nerolidol, L-limonene and beta-ionone was reduced. Furthermore, behavioral assays revealed consistent patterns among these compounds, especially for nerolidol, with adults could no longer able to differentiate 0.1% nerolidol from controls. RNAi experiments suggest that at least in part, CmedOBP14 mediates the ability to smell nerolidol and beta-ionone.

NixCoy/H-ZrO2 catalysts composed of highly dispersed NixCoy nanoparticles supported by mesoporous ZrO2 hollow sphere are synthesized by templating and impregnation processes. According to thermogravimetric analysis, X-ray photoelectron spectroscopy, and dry reforming results, a synergetic reaction mechanism is proposed to explain the better performance of alloy catalysts compared to Ni/H-ZrO2 or Co/H-ZrO2. In dry reforming of methane (DRM) reaction, Ni and Co act as catalysts for CH4 cracking and CO2 reduction, respectively, and the induced carbon deposits on Ni can be oxidized by the active oxygen left on Co, which regenerate the metal surface for the following reaction. Among all the alloy catalysts, the Ni0.8Co0.2/H-ZrO2 catalyst presents the highest activity and stability because the strong metal-support interaction prevents the sintering of nanocatalysts at high temperature and the hollow structure enhances the mass transportation of reactants and products. More importantly, Ni and Co can synergistically balance the speed of CH4 cracking and CO2 reduction, which effectively avoid coke accumulation/catalyst oxidation and ensure fast and stable conversion for DRM reaction.

Fructosyltransferases have been used in the industrial production of fructooligosaccharides (FOS). However, it is still not possible to explain the difference in FOS production based on the variations observed in the FOS synthesizing enzymes of A. niger. In the present study, a novel fructosyltransferase (FT-A) from A. niger TCCC41686 with high FOS synthesis ability was characterized. The FT-A gene was obtained and expressed in Pichia pastoris. A homology model of FT-A showed that the changes of residues identified outside the conserved domains were found to have an effect on its characteristics and its FOS-synthesis capacity. The optimal activity of the recombinant FT-A was observed at 50 °C and pH 6.0, and it was stable below 50 °C and over the range of pH 3.0–11.0. The Km and Vmax values of FT-A were 151.13 g L−1 and 6.55 g L−1 min−1, respectively. The production of FOS using the recombinant FT-A remained above 60% during 50–80 min of synthesis based on sucrose as substrate. The novel fructosyltransferase (FT-A) investigated in this study can potentially be applied for the efficient industrial production of FOS. The results also provide more valuable information for explaining the relationship between the structure and function of the FT-A.

Metformin is currently the most prescribed oral agent for diabetes treatment; however the overdose or long-term use may cause some severe side effects such as liver injury. Researches indicate that metformin-induced liver injury is closely related to upregulation of hepatic H2S. Hence, monitoring hepatic H2S generation induced by metformin could be an effective approach for evaluating hepatoxicity of the drug. Methods: We present a novel turn-on and dual-mode probe for detecting and imaging metformin-induced liver injury by specifically tracking the upregulation of hepatic H2S with fluorescent and optoacoustic methods. After reaction with H2S, the strong electron-withdrawing group dinitrophenyl ether (which acts as both the recognition moiety and the fluorescence quencher) was cleaved and replaced by an electron-donating group hydroxyl. This correspondingly leads to the changes of the probe's electronic state and absorption red-shifting as well as the subsequent turn-on fluorescent and optoacoustic signals. Results: The probe was applied to the colon tumor-bearing mice model and the metformin-induced liver injury mice model to achieve tumor imaging and liver injury assessment. The biosafety of the probe was verified by histological analysis (hematoxylin and eosin staining) and serum biochemical assays. Conclusion: The probe responds quickly to H2S in tumors and the liver, and MSOT imaging with the probe offers cross-secitonal and 3D spatial information of liver injury. This study may provide an effective approach for accessing medication side effects by tracking drug-metabolism-related products.

Hypoxia is a key hallmark of solid tumors and tumor hypoxia usually contributes to cancer progression, therapeutic resistance and poor outcome. Accurately detecting and imaging tumor hypoxia with high spatial resolution would be conducive to formulating optimized treatment plan and thus achieving better patient outcome. Methods: Tumor hypoxia can cleave the azo linker and release a NIR fluorophore (NR-NH2) and release the active drug as well. NR-NH2 shows a strong absorption band at around 680 nm and a strong fluorescence band at 710 nm, allowing for both multispectral optoacoustic tomography imaging (MSOT) and fluorescent imaging of tumor hypoxia in a tumor-bearing mouse model. Results: Liposome encapsulated with the activatable chromophore (NR-azo) for detecting/imaging tumor hypoxia and for tumor inhibition was demonstrated. For this chromophore, a xanthene-based NIR fluorophore acts as the optoacoustic and fluorescent reporter, an azo linker serves as the hypoxia-responsive moiety and a nitrogen mustard as the therapeutic drug. NR-azo shows an absorption at around 575 nm but exhibits negligible fluorescence due to the existence of the strong electron-withdrawing azo linker. Conclusion: We demonstrated an optoacoustic and fluorescent system for not only imaging tumor hypoxia in vivo but also achieving tumor inhibition.

Qiaoping Li,1,* Ziwei Huang,2,* Defu Liu,3 Jingna Zheng,1 Jianhui Xie,4– 6 Jiannan Chen,1 Huifang Zeng,2 Ziren Su,1 Yucui Li1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China; 3School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 4The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yucui Li; Ziren SuGuangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaTel +86 20 39358517Fax +86 20 39358390Email liyucui@gzucm.edu.cn; suziren@gzucm.edu.cnPurpose: Berberine (BBR) is an active component of Phellodendri Cortex (PC), which is a traditional Chinese medicine that has been prescribed clinically for hyperuricemia (HUA) for hundreds of years. Many studies reported the anti-inflammatory and nephroprotective properties of BBR and PC; however, the therapeutic effects of BBR on HUA have not been explored. This study aims to investigate the efficacy and mechanism of BBR for treating HUA.Methods: The mechanism of BBR in the treatment of HUA were predicted by network pharmacology. A mouse model of HUA established by potassium oxonate and hypoxanthine was used to verify the prediction. The levels of serum uric acid (UA), urea nitrogen (BUN) and creatinine (CRE) were determined by biochemical test kits. Hematoxylin and eosin staining of kidney tissues was used to observe the kidney damage. ELISA kits were applied to detect the levels of interleukin (IL)-1β and IL-18 in serum and kidney tissues. Quantitative real-time PCR and Western blotting were adopted to analyze the expression of NLRP3, ASC, Caspase1, IL-1β and URAT1. The expressions of URAT1 in the kidney tubules were visualized by immunohistochemical staining. Molecular docking was used to assess the interaction between URAT1 and BBR.Results: The network pharmacology screened out 82 genes and several inflammation-related signaling pathways related to the anti-hyperuricemia effect of BBR. In the in vivo experiment, BBR substantially decreased the level of UA, BUN and CRE, and alleviated the kidney damage in mice with HUA. BBR reduced IL-1β and IL-18, and downregulated expressions of NLRP3, ASC, Caspase1 and IL-1β. BBR also inhibited expression of URAT1 and exhibited strong affinity with this target in silico docking.Conclusion: BBR exerts anti-HUA and nephroprotective effects via inhibiting activation of NLRP3 inflammasome and correcting the aberrant expression of URAT1 in kidney. BBR might be a novel therapeutic agent for treating HUA.Keywords: berberine, hyperuricemia, URAT1, NLRP3 signaling pathway

Whole plants of Gentianella turkestanorum are commonly used as a traditional Uighur medicine. A phytochemical investigation led to the isolation of eight undescribed gentianellane-type sesterterpenoids (18-epi-nitidasin, gentianelloids D−F, and 18-epi-gentianelloids C–F), one undescribed 11,12-seco-gentianellane (18-epi-alborosin), and three known analogs (nitidasin, gentianelloid C and alborosin) among which gentianelloid C was found for the first time from a natural source. The structures of these compounds were elucidated by extensive spectroscopic analyses (including 1D and 2D NMR, HRMS, IR, and specific rotation) and in the case of 18-epi-gentianelloid C by the single-crystal X-ray diffraction analysis. A putative biosynthetic route for these sesterterpenoids was proposed. The immunosuppressive activity of the isolated compounds was also evaluated by their ability to inhibit the proliferation of T cells and T cell cytokine IFN-γ production. Nitidasin suppressed IFN-γ production with an IC50 value of 16.50 μM, while gentianelloid F and alborosin inhibited the proliferation of and IFN-γ production in T cells with IC50 values of 12.40–14.66 μM.

Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo. The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic β-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.

The latest research has indicated that anti-tumor agents with COX-2 inhibitory activity may benefit their anti-tumor efficiency. A series of sclerotiorin derivatives have been synthesized and screened for their cytotoxic activity against human lung cancer cells A549, breast cancer cells MDA-MB-435 using the MTT method. Among them, compounds 3, 7, 12, 13, 15, 17 showed good cytotoxic activity with IC50 values of 6.39, 9.20, 9.76, 7.75, 9.08, and 8.18 &mu, M, respectively. In addition, all compounds were tested in vitro the COX-2 inhibitory activity. The results disclosed compounds 7, 13, 25 and sclerotiorin showed moderate to good COX-2 inhibition with the inhibitory ratios of 58.7%, 51.1%, 66.1% and 56.1%, respectively. Notably, compound 3 displayed a comparable inhibition ratio (70.6%) to the positive control indomethacin (78.9%). Furthermore, molecular docking was used to rationalize the potential of the sclerotiorin derivatives as COX2 inhibitory agents by predicting their binding energy, binding modes and optimal orientation at the active site of the COX-2. Additionally, the structure-activity relationships (SARS) have been addressed.

Background Berberine (BBR) has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The metabolites of BBR were believed to contribute significantly to its pharmacological effects. Oxyberberine (OBB), a gut microbiota-mediated oxidative metabolite of BBR, has been firstly identified in our recent work. Purpose Here, we aimed to comparatively investigate the anti-NAFLD properties of OBB and BBR. Methods The anti-NAFLD effect was evaluated in high-fat diet-induced obese NAFLD rats with biochemical/ELISA tests and histological staining. The related gene and protein expressions were detected by qRT-PCR and Western blotting respectively. Molecular docking and dynamic simulation were also performed to provide further insight. Results Results indicated OBB remarkably and dose-dependently attenuated the clinical manifestations of NAFLD, which (100 mg/kg) achieved similar therapeutic effect to metformin (300 mg/kg) and was superior to BBR of the same dose. OBB significantly inhibited aberrant phosphorylation of IRS-1 and up-regulated the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction. Meanwhile, OBB treatment remarkably alleviated inflammation via down-regulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, while enhancing Arg1 mRNA expression in white adipose tissue. Moreover, OBB exhibited closer affinity with AMPK in silicon and superior hyperphosphorylation of AMPK in vivo, leading to increased ACC mRNA expression in liver and UCP-1 protein expression in adipose tissue. Conclusion Taken together, compared with BBR, OBB was more capable of maintaining lipid homeostasis between liver and WAT via attenuating hepatic insulin pathway and adipocyte inflammation, which was associated with its property of superior AMPK activator.

The chemoenzymatic remodeled monoclonal antidodies with well-defined glycan structure at the Fc domain display improved biological activities, such as ADCC and ADCP, and are more likely to yield a better safety profile by eliminating the non-human glycans derived from CHO cell culture. We covalently immobilize wild type endoglycosidase S (EndoS), fucosidase, and EndoS2 mutant on magnetic beads through a linker to efficiently generate homogeneous antibody glycoforms without additional purification step to remove endoglycosidase and fucosidase. We also used the biotinylated wild type EndoS2 and EndoS2 mutant in combination with covalently immobilized fucosidase on magnetic beads to allow the sequential removal of endoglycosidases and fucosidase for efficient glyco-engineering and isolation of antibodies without purifying deglycosylated antibody intermediate. Notably, the relatively expensive fucosidase can be recovered to reduce the cost, and the strong affinity of streptavidin to biotin would complete the isolation of biotinylated enzymes. We used Trastuzumab as a model to demonstrate both approaches were reliable for the large-scale production and isolation of antibodies without the residual contamination of endoglycosidase to avoid deglycosylation over storage time.

Saturated fatty acids with different chain lengths have different biological activities, but little is known about very-long-chain saturated fatty acids (VLCSFAs). This study investigated the associations between the circulating VLCSFAs and cardiovascular health. This community-based cohort study included 2198 adults without carotid artery plaques (CAPs) at baseline. The percentage of baseline erythrocyte VLCSFA (arachidic acid (C20:0), behenic acid (C22:0), and lignoceric acid (C24:0)) was measured by gas chromatography. The presence of CAPs was determined at baseline and every 3 years thereafter by ultrasound examination. A meta-analysis was conducted to summarize the pooled associations between circulating VLCSFAs and the risk of cardiovascular diseases (CVDs). During a median of 7.2 years of follow-up, 573 women (35.1%) and 281 men (49.6%) were identified as CAP incident cases. VLCSFAs were inversely related with CAP risk in women (all p-trend &lt, 0.05) but not in men. Multivariate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of CAPs for the highest (vs. lowest) quartile were 0.80 (0.63&ndash, 1.01) for C20:0, 0.71 (0.56&ndash, 0.89) for C22:0, 0.75 (0.59&ndash, 0.94) for C24:0, and 0.69 (0.55&ndash, 0.87) for total VLCSFAs in women. The pooled HRs (95% CIs) of CVDs for the highest (vs. lowest) circulating VLCSFAs from seven studies including 8592 participants and 3172 CVD events were 0.67 (0.57&ndash, 0.79) for C20:0, 0.66 (0.48&ndash, 0.90) for C22:0, and 0.57 (0.42&ndash, 0.79) for C24:0, respectively. Our findings suggested that circulating VLCSFAs were inversely associated with cardiovascular health.

OBJECTIVE To examine the association of erythrocyte n-6 polyunsaturated fatty acid (PUFA) biomarkers with incident type 2 diabetes and explore the potential role of gut microbiota in the association. RESEARCH DESIGN AND METHODS We evaluated 2,731 participants without type 2 diabetes recruited between 2008 and 2013 in the Guangzhou Nutrition and Health Study (Guangzhou, China). Case subjects with type 2 diabetes were identified with clinical and biochemical information collected at follow-up visits. Using stool samples collected during the follow-up in the subset (n = 1,591), 16S rRNA profiling was conducted. Using multivariable-adjusted Poisson or linear regression, we examined associations of erythrocyte n-6 PUFA biomarkers with incident type 2 diabetes and diversity and composition of gut microbiota. RESULTS Over 6.2 years of follow-up, 276 case subjects with type 2 diabetes were identified (risk 0.10). Higher levels of erythrocyte γ-linolenic acid (GLA), but not linoleic or arachidonic acid, were associated with higher type 2 diabetes incidence. Comparing the top to the bottom quartile groups of GLA levels, relative risk was 1.72 (95% CI 1.21, 2.44) adjusted for potential confounders. Baseline GLA was inversely associated with gut microbial richness and diversity (α-diversity, both P < 0.05) during follow-up and significantly associated with microbiota β-diversity (P = 0.002). α-Diversity acted as a potential mediator in the association between GLA and type 2 diabetes (P < 0.05). Seven genera (Butyrivibrio, Blautia, Oscillospira, Odoribacter, S24-7 other, Rikenellaceae other, and Clostridiales other) were enriched in quartile 1 of GLA and in participants without type 2 diabetes. CONCLUSIONS Relative concentrations of erythrocyte GLA were positively associated with incident type 2 diabetes in a Chinese population and also with gut microbial profiles. These results highlight that gut microbiota may play an important role linking n-6 PUFA metabolism and type 2 diabetes etiology.

Background: Coronavirus disease-2019 (COVID-19) spreads rapidly throughout the world. So far, no therapeutics have yet been proven to be effective. Ribavirin was recommended for the treatment of COVID-19 because of its in vitro activity. However, evidence supporting its clinical use with good efficacy is still lacking.Methods: A total of 208 confirmed severe or critical COVID-19 patients who were hospitalized in Wuhan Union West Campus between 1 February 2020 and 10 March 2020 were enrolled in the retrospective study. Patients were divided into two groups based on the use of ribavirin. The primary endpoint was the time to clinical improvement. The secondary endpoints included mortality, survival time, time to throat swab SARS-CoV-2 nucleic acid negative conversion, and hospital duration.Results: 68 patients were treated with ribavirin while 140 not. There were no significant between-group differences in demographic characteristics, baseline laboratory test results, treatment, and distribution of ordinal scale scores at enrollment, except coexisting diseases especially cancer (ribavirin group vs no ribavirin group, P = 0.014). Treatment with ribavirin was not associated with a difference in the time to clinical improvement (P = 0.483, HR = 0.884, 95% CI = 0.627-1.247). There were also no significant differences between-group in the number of patients with SARS-CoV-2 nucleic acid negative conversion, mortality, survival time, and hospital duration. Conclusion: In hospitalized adult patients with severe or critical COVID-19, no significant benefit was observed with ribavirin treatment.

The expression and localization of different isoforms of creatine kinase in Pelodiscus sinensis (PSCK) were studied to reveal the role of PSCK isozymes (PSCK-B, PSCK-M, PSCK-S) under bacterial infection-induced immunologic stress. The computational molecular dynamics simulations predicted that PSCK-S would mostly possess a kinase function in a structural aspect when compared to PSCK-B and PSCK-M. The assay of biochemical parameters such as total superoxide dismutase (T-SOD), lactate dehydrogenase (LDH), malondialdehyde (MDA), catalase (CAT), and the content of ATP were measured along with total PSCK activity in different tissue samples under bacterial infection. The expression detections of PSCK isozymes in vitro and in vivo were overall well-matched where PSCK isozymes were expressed differently in P. sinensis tissues. The results showed that PSCK-B mostly contributes to the spleen, followed by the liver and myocardium; PSCK-M mostly contributes to the liver, followed by the myocardium and skeletal muscle, while PSCK-S contributes to the spleen and is uniquely expressed in skeletal muscle. Our study suggests that the various alterations of PSCK isozymes in tissues of P. sinensis are prone to defense the bacterial infection and blocking energetic imbalance before severe pathogenesis turned on in P. sinensis.

Compared to the generation of singlet oxygen in photodynamic therapy, photo-generation of nitric oxide (NO) would not be limited by the concentration of molecular oxygen. However, therapeutic applications of exogenous nitric oxide are usually limited by its short half-life and its vulnerability to many biological substances, thus straightforward and precise control over NO delivery may be critical to its therapeutic effects. Herein, we demonstrate a mitochondrial-targeting and photoactive NO-releasing system as an anticancer drug. Fabricated by covalently incorporating a photo-responsive NO-donor and a mitochondrial targeting ligand onto carbon dots, this nanosystem exhibits a multi-functional nature which combines mitochondrial-targeting, photocontrollable NO-releasing and cell imaging. Upon cellular internalization, the nanosystem could target mitochondria effectively. Furthermore, the system displays little dark toxicity under physiological temperature; but upon light irradiation, it could release NO, efficiently damage mitochondria and consequently cause prominent apoptosis of cancer cells. Moreover, evaluated by using MTT assay, this nanosystem shows high cytotoxicity towards two cancer cell lines. These observations provide new insights for exploiting NO in disease therapy.

Clinical drug-induced organ toxicity and damage have been recognized as an important public health issue, and an effective approach capable of in vivo detection of biomarkers resulting from drug-induced organ damage is being actively pursued. Herein, we demonstrate a ratiometric fluorescent probe that can trace the variation in alkaline phosphatase (ALP, an organ damage biomarker) levels spatially in vivo. The probe was synthesized by incorporating a phosphate group and an amine-N-oxide group on a 1,8-naphthalimide derivative. The presence of ALP cleaves the phosphate group from naphthalimide and remarkably alters the probe's photophysical properties, thus achieving ratiometric detection of ALP. The incorporation of amine-N-oxide ensures excellent water solubility and biocompatibility, which guarantees the ratiometric detection of ALP in aqueous media and in the cells overexpressed with ALP. With a detection limit of 0.38 U L−1, the probe was successfully used in detecting ALP in human serum samples. Moreover, the probe can be employed to monitor and spatially map the endogenous variation in ALP levels in zebrafishes. This is the first observation, to our knowledge, of organ-scale ALP pattern in vivo as a result of clinical drug (APAP) induced damage.

IntroductionMany clinical trials showed favorable effects of high-doses supplemental n-3 polyunsaturated fatty acids (PUFA) on cardio-metabolic risk factors. However, limited studies examined the prospective associations of circulating n-3 PUFA with body fat and its distribution, metabolic syndrome (MS), carotid atherosclerosis, and nonalcoholic fatty liver disease (NAFLD) in subjects with habitual diets containing low levels of n-3 PUFA.Materials and MethodsThis community-based prospective study enrolled 4048 participants (40–75 years) at baseline (2008–2010, 2013) from Guangzhou, China. They were followed-up approximately once every 3 years. Fatty acids in erythrocyte membranes were measured at baseline. We determined metabolic syndrome factors, body fat by DXA scanning, carotid intima-media thickness (IMT) and NAFLD by ultrasound at the visits. General information, anthropometric indices, habitual dietary intake and other covariates were assessed at each visit.ResultsAmong the total 4048 subjects, 3075 and 2671 subjects had erythrocyte n-3 PUFA data and completed the first and second follow-ups. Generally, erythrocyte n-3 PUFA were favorably associated with body fat (particularly at abdomen) and its changes, and with the presence and incidence of MS, type 2 diabetes, carotid IMT thickening. The participants with the highest (vs lowest) quartile of n-3 PUFA were associated with -5.81% fat mass (p < 0.001) and -2.11% of fat mass change at the abdomen (Android) area. The adjusted hazards ratios (95% CI) for the highest (vs. lowest) group were 0.74 (0.61, 0.89) (total n-3 PUFA), 0.71 (0.59, 0.86) (docosahexaenoic acid, DHA), 0.78 (0.65, 0.95) (docosapentaenoic acid, DPA), 1.96 (1.60, 2.40) (gamma-linolenic acid, GLA) for MS; 0.70(0.55, 0.90) (total n-3 PUFA), 0.67(0.52,0.87) (DHA) and 0.73(0.57,0.93) (DPA) for bifurcation IMT thickening, 0.57(0.38, 0.86) (eicosapentaenoic acid, EPA) and 0.63 (0.41, 0.95) (DPA) for type 2 diabetes, and 1.18 (1.09, 1.33) (DHA) for alleviated NAFLD. Both higher levels of total and individual marine n-3 PUFAs (DHA, EPA and DPA) were associated with lower blood pressure at baseline and lower changes in diastolic and systolic blood pressure over the follow-up period. Plant n-3 PUFA (α-linolenic acid, ALA) largely had less significant association with the above-mentioned indices as compared with marine n-3 PUFAs.DiscussionHigher proportions of erythrocyte n-3 PUFA (particularly marine sources) was associated with lower body fat, blood pressure and their changes, and lower risks of MS, type 2 diabetes and bifurcation IMT thickening, but higher chance of alleviated NAFLD in middle-aged and older adults.

Alkaline phosphatase (ALP) is associated with many diseases, and its accurate detection is of great significance. Fluorescent compounds with aggregation-induced emission (AIE) feature show beneficial advantages for serving as fluorescent probes. Herein, an AIE-active "turn on" probe for ALP detection was synthesized through incorporating a strong electron-withdrawing group (cyano) in the middle and the recognition moiety phosphate group at the end, thereby rendering a D-A-D structure with a relatively high conjugation degree and good water solubility. It was found that the probe TPE-CN-pho is highly sensitive to ALP in aqueous solution. In the presence of ALP, the hydrophilic phosphate group on the probe is rapidly removed, resulting in a decrease in water solubility and subsequent formation of aggregates, thereby achieving aggregation-induced emission. Moreover, the probe TPE-CN-pho has also been successfully applied to imaging ALP in living cells.

Objectives. Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication. Methods. Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments. Results. A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain. Conclusions. Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

Viscosity is an important quality parameter for fluid drinks, which can serve as an indicator for the extent of food spoilage, since the viscosity of fluid drinks varies during the spoilage process. In this study, a near-infrared fluorophore based on tetranitrile-anthracene (TPAEQ) was designed for viscosity determination via aggregation-induced emission (AIE). With increased viscosity, TPAEQ showed enhanced emission at around 759 nm with a large Stokes shift of 195 nm in water. The probe TPAEQ was successfully used to monitor the viscosity changes during the food spoilage process for fluid drinks. Moreover, the probe TPAEQ has effectively been utilized to determine the mass concentrations of food thickeners added in the real fruit drinks. The approach for the viscosity determination could enable the on-site direct detection with convenient operation in food safety inspection applications.

Melanoma is a type of highly malignant and metastatic skin cancer, and early detection of melanoma by analyzing the level of its biomarker may decrease the likelihood of mortality. In this study, a fluorescent probe called NBR-AP for detecting tyrosinase (a biomarker of melanoma) has been created by incorporating a hydroxyphenylurea group (as a substrate for the enzyme) onto a fluorescent dye phenoxazine derivative (as an activatable signal reporter). This probe can be activated to generate fluorescence through a tyrosinase-mediated oxidation followed by hydrolysis of the urea linkage. The probe is able to detect the endogenous tyrosinase level in live cells and in zebrafish sensitively and selectively. Moreover, by imaging the tyrosinase activity, NBR-AP has been successfully applied to diagnose the melanoma and its metastasis in xenogeneic mouse models established via subcutaneous injection of B16F10 cells.

This study aimed to investigate the prophylactic effect of selenium-enriched Cordyceps militaris (CS) against triptolide-induced acute hepatotoxicity. Rats were intragastrically administrated with CS and ordinary Cordyceps militaris (CM) for 7 consecutive days prior to triptolide intoxication. Triptolide elevated levels of serum aminotransferases, total cholesterol and caused severe liver injury. However, CS remarkably inhibited the increases of these parameters and pathological damages. The action mechanisms might be associated with its antioxidant property by enhancing antioxidant enzymes activities and triggering nuclear factor E2-related factor 2 (Nrf2) translocation and downstream genes expression. Besides, CS prevented cellular apoptosis through up-regulating Bcl-2/Bax ratio and down-regulating cytochrome c and caspase-3 cleavage. Constituent analyses showed that CS had higher amounts of cordycepin, selenium, selenocystine and polysaccharides than CM. In conclusion, CS effectively prevented triptolide-induced hepatotoxicity via activating Nrf2 pathway and inhibiting hepatocyte apoptosis, suggesting that it could be a promising hepatic protector and a befitting nutraceutical supplement.

Mechanism studies have suggested that carotenoids may benefit bone health due to their antioxidant properties, but epidemiological data on their effects on risk of hip fracture are sparse.To explore the relationships between dietary total and specific carotenoids and the risk of hip fracture in a middle-aged and elderly Chinese population.A case-control study of 1070 patients with hip fractures (diagnosed within 2 weeks) aged 55-80 years and 1070 age- (within 3 years) and gender-matched controls was conducted in Guangdong, China between 2009 and 2015. Information on dietary carotenoid intake was assessed using a 79-item food frequency questionnaire administered in face-to-face interviews, and general information was collected using structured questionnaires. The univariate and multivariate conditional logistic regression models were applied to analyze the associations.Higher intakes of both total and some specific carotenoids (including β-carotene, β-cryptoxanthin and lutein/zeaxanthin) were significantly associated with a lower risk of hip fracture (all p trends0.01). Compared with the lowest quartile of carotenoids, the multivariate-adjusted odds ratios and 95% confidential intervals of the highest quartile were 0.44 (0.29, 0.68) (total carotenoids), 0.50 (0.29, 0.69) (β-carotene), 0.55 (0.38, 0.80) (β-cryptoxanthin) and 0.40 (0.27, 0.59) (lutein/zeaxanthin), respectively. There were no statistically significant associations between α-carotene and lycopene intakes and hip fracture risk after adjustment for various confounding variables.These results suggest that the consumption of carotenoids may be protective against hip fracture in middle-aged and elderly Chinese adults.

Shale oil is currently of interest for unconventional resource exploration and development. Understanding the mechanism of interaction between the complex mixture of organic compounds in shale oil and minerals making up the reservoir rock-oil interface will assist recovery. In this study, molecular dynamics simulation is used to study the adsorption characteristics of a model oil mixture within nanoscale intra-particle pores of kaolinite minerals, which form pore filling structures in shale rock. To better understand the effects of oil composition, temperature and pressure on the adsorption properties of the model oil mixture, a range of temperatures (298 K, 323 K, 348 K and 373 K) and pressures (1 bar, 50 bar, 100 bar and 200 bar) representing up to reservoir conditions were used. This study shows that adsorption and arrangement of oil molecules is dependent on the surface of kaolinite and the distance away from it. The simulations show polar compounds are likely to be adsorbed on aluminol kaolinite basal surfaces, while alkanes preferentially adsorb on silicate surfaces. In addition, the number of oil molecule bound layers, and total adsorption amount on the silicate surface is greater than the aluminol surface. The density of adsorbed oil is reduced with increase in temperature, while the effect of pressure is not as significant. On the basis of performed molecular simulations, we show the adsorption rate of shale oil on the surfaces of kaolinite sheets and assess the removable capacity of the model oil. Keywords: shale oil, molecular dynamics, clay mineral, recovery.

Aims The aim of this study was to comparatively investigate the potential gastroprotective effect and underlying mechanisms of coptisine free base (CFB, 8-hydroxy-7, 8-dihydrocoptisine), berberine and lansoprazole against indomethacin-induced gastric ulcer in rats. Materials and methods CFB (10, 20 and 40 mg/kg), berberine (20 mg/kg) and lansoprazole (30 mg/kg) were orally administrated to rats prior to indometacin ingestion, and gastric lesions were evaluated macroscopically and histologically, and further analyzed by ELISA, qRT-PCR and Western blot. Key findings CFB exerted comparable or superior gastroprotective effect to berberine in protecting against indomethacin-induced gastric injury. CFB pretreatment significantly enhanced the levels of superoxide dismutase (SOD) and glutathione (GSH), and markedly decreased the malonaldehyde (MDA) content. CFB administration effectively suppressed the levels of myeloperoxidase (MPO), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II). Besides, CFB substantially up-regulated the mRNA expressions of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and promoted gastric mucosal prostaglandin E2 level (PGE2). Furthermore, CFB pretreatment remarkably increased the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) from cytosol into the nucleus, and the expression of heme oxygenase-1 (HO-1), while significantly decreased the expression of mitogen activated protein Kinase Kinase 6 (MKK6) and translocation of p38 mitogen-activated protein kinase (p38 MAPK). Significance This was the first investigation reporting the anti-ulcer effect of protoberberine alkaloid free base on in vivo rodent model. The gastroprotective mechanism of CFB might involve favorable regulation of antioxidant and anti-inflammatory status mediated, at least partially, by the Nrf2 signaling pathway and p38 MAPK translocation.

Scanning electron microscopy (SEM) is one of the most prevalent methods used to image and quantify the pore size distribution of shale rock, critical in understanding unconventional petroleum systems and production. Generally, digital greyscale SEM images of shale are currently processed for pore quantification either by a manual drawing method, manual threshold method, automatic threshold method, edge detection or watershed methods, all of which have some limitations that impact the quality of pore extraction results. A new, Edge-Threshold Automatic Processing (ETAP) method is reported here to enable robust extraction and quantification of pore data in shale images. Image pre-treatment makes the greyscale of regions brighter than that of kerogen set to the peak value of kerogen greyscale. The pore image is subsequently obtained using an edge detection method. A discriminant function has been designed to determine the best threshold of the greyscale image to obtain the pore image. Finally, combination of both processed pore images gives the final pore image. Our new method overcomes the impact of kerogen, mineral, roughness and artificial debris caused by pre-treatment of samples, which potentially introduce errors using alternative methods. We compare our new method to a systematic manual drawing method. The processing results through ETAP provide reliable results, and gets the highest value of 0.7466 using a discriminant function Qt, compared with the automatic threshold methods, the edge detection method and watershed method. The application of the ETAP method on shale samples of the Longmaxi Formation and Qiongzhusi Formatiosn in Sichuan basin shows that samples from the Longmaxi Formation have more organic pores than that of the Qiongzhusi Formation, however a larger size of inorganic pores develop in the Qiongzhusi shale. This indicates that shale of the Longmaxi Formation has better reservoir properties and reliable preservation conditions.

Numerous studies have unveiled the importance of nitrogen (N) transformation processes over the past decades, but comprehensive studies of key N-cycling processes are still rare in estuarine and coastal ecosystems. Here, we used isotope pairing, isotope-tracing, and isotope dilution techniques combined with quantitative polymerase chain reaction to investigate microbial N-cycling processes in surface sediments (0–5 cm) of the Pearl River Estuary. The average rates of denitrification, anammox, DNRA, N2 fixation, N mineralization, and NH4+ immobilization were 1.41 ± 0.89, 0.067 ± 0.033, 0.47 ± 0.28, 0.31 ± 0.30, 1.86 ± 1.09, and 1.30 ± 0.83 μg N g−1 dry d−1, respectively. Sediment grain size, organic matter, nutrients, and Fe2+/Fe3+ rather than gene abundances controlled these rates. The abundances of bacterial 16S rRNA, anammox 16S rRNA, nirS, nrfA, nifH, bacteria-amoA, and archaea-amoA genes were significantly correlated with organic matter, nutrients, and sediment grain size. In general, higher rates and gene abundance was occurred in outer than inner estuary. Among these pathways, denitrification contributed 41.83–90.13% of the total nitrate reduction, as compared to 0.94–8.58% for anammox and 8.55–54.56% for DNRA. The sediment N-loss fluxes caused by denitrification and anammox in our study area (1.5 × 1010 m2) was about 6.2 × 107 mol N d−1, accounting for ~42.1% of the riverine dissolved inorganic N fluxes, suggesting that the sediment of the Pearl River Estuary has great significance to the mitigation and controlling of N pollution in this ecosystem. Additionally, the net NH4+ production via sediment microbial pathways (N mineralization, N2 fixation, DNRA, NH4+ immobilization, and anammox) was estimated at ~ 5.5 × 107 mol N d−1, while the net NO3− consumption (denitrification, anammox, and DNRA) was ~8.3 × 107 mol N d−1. Overall, these results highlight the importance of complicated N-cycling processes in controlling the N budget in the Pearl River Estuary and improve the understanding of both the processes and associated controlling factors in estuarine and coastal ecosystems.

Objective: To assess the correlation between Serum phospholipase A2 receptor antibody and clinicopathological features in patients with membranous nephropathy. Method: The patients being hospitalized for renal biopsy were selected in this study from January 2016 to January 2018. And normal controls were randomly selected; all the patients were divided into idiopathic membranous nephropathy and non-idiopathic membranous nephropathy groups; patients with idiopathic membranous nephropathy were divided into three groups, namely stage I, stage II and stage III; using software for statistical analysis. Results: A total of 357 patients were enrolled, including 155 patients with idiopathic membranous nephropathy, 183 patients with non-idiopathic membranous nephropathy, and 19 cases for normal controls. The average age of the idiopathic membranous nephropathy (IMN) group is higher than that of the membranous nephropathy group (P = 0.01). Different pathological stages of idiopathic membranous nephropathy general clinical characteristics analysis results showed that the age, cys c, serum creatinine (Scr) in stage III membranous nephropathy group were higher than those of the stage I and II membranous nephropathy (P values were 0.003, 0.000 and 0.000 respectively); titers of serum phospholipase A2 receptors antibody with stage II and III membranous nephropathy higher than the stage I membranous nephropathy group (P = 0.006); serum albumin (Alb) levels correlated inversely with serum anti-PLA2R antibody titers (rs = –0.234, P = 0.003), serum antiphospholipase A2 receptor (PLA2R) antibody titer level in patients with idiopathic membranous nephropathy was significantly higher than that in patients with non-membranous nephropathy (P < 0.001). Conclusion: Baseline titer of serum anti-PLA2R antibody is negatively correlated with Alb in the IMN patients，and serum anti-PLA2R antibody level in patients with stage I IMN was significantly lower than stage II and III IMN patients.

Background Exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy has been suggested to be associated with adverse pregnancy and birth outcomes; however, the findings have been inconsistent. We aimed to conduct a systematic review and meta-analysis to provide an overview of these associations. Methods The online databases PubMed, EMBASE and Web of Science were searched comprehensively for eligible studies from inception to February 2021. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random- or fixed-effects models, and dose-response meta-analyses were also conducted when possible. Findings A total of 29 studies (32,905 participants) were included. The pooled results demonstrated that perfluorooctane sulfonate (PFOS) exposure during pregnancy was linearly associated with increased preterm birth risk (pooled OR per 1-ng/ml increase: 1.01, 95% CIs: 1.00–1.02, P = 0.009) and perfluorononanoate (PFNA) and perfluorooctanoate (PFOA) exposure showed inverted U-shaped associations with preterm birth risk (P values for the nonlinear trend: 0.025 and 0.030). Positive associations were also observed for exposure to perfluorodecanoate (PFDA) and miscarriage (pooled OR per 1-ng/ml increase: 1.87, 95% CIs: 1.15–3.03) and PFOS and preeclampsia (pooled OR per 1-log increase: 1.27, 95% CIs: 1.06–1.51), whereas exposure to perfluoroundecanoate (PFUnDA) was inversely associated with preeclampsia risk (pooled OR per 1-log increase: 0.81, 95% CIs: 0.71–0.93). Based on individual evidence, detrimental effects were observed between PFDA exposure and small for gestational age and between PFOA and PFOS and intrauterine growth restriction. No significant associations were found between pregnancy PFAS exposure and other adverse pregnancy outcomes (i.e., gestational diabetes mellitus, pregnancy-induced hypertension, low birth weight, and large and small for gestational age). Interpretation Our findings indicated that PFOS, PFOA and PFNA exposure during pregnancy might be associated with increased preterm birth risk and that PFAS exposure might be associated with the risk of miscarriage and preeclampsia. Due to the limited evidence obtained for most associations, additional studies are required to confirm these findings.

Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, C15H26O) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days. The mice were then given PA (10, 20 and 40mg/kg) or sulfasalazine (SASP, 200mg/kg) as positive control via oral administration for 7 days. At the end of study, animals were sacrificed and samples were collected for pathological and other analysis. In addition, a metabolite profiling and a targeted metabolite analysis, based on the Ultra-Performance Liquid Chromatography coupled with mass spectrometry (UPLC-MS) approach, were performed to characterize the metabolic changes in plasma. The results revealed that PA significantly reduced the disease activity index (DAI) and ameliorated the colonic injury of DSS mice. The levels of colonic MPO and cytokines involving TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10 also declined. Furthermore, PA improved the intestinal epithelial barrier by enhancing the level of colonic expression of the tight junction (TJ) proteins, for instance ZO-1, ZO-2, claudin-1 and occludin, and by elevating the levels of mucin-1 and mucin-2 mRNA. The study also demonstrated that PA inhibited the DSS-induced cell death signaling by modulating the apoptosis related Bax and Bcl-2 proteins and down-regulating the necroptosis related RIP3 and MLKL proteins. By comparison, up-regulation of IDO-1 and TPH-1 protein expression in DSS group was suppressed by PA, which was in line with the declined levels of kynurenine (Kyn) and 5-hydroxytryptophan (5-HTP) in plasma. The therapeutic effect of PA was evidently reduced when Kyn was given to mice. In summary, the study successfully demonstrated that PA ameliorated DSS-induced mice acute colitis by suppressing inflammation, maintaining the integrity of intestinal epithelial barrier, inhibiting cell death signaling, and suppressing tryptophan catabolism. The results provided valuable information and guidance for using PA in treatment of UC.

The clinical applications of tradition prodrug are restricted to a certain extent due to its some defects such as side effects, low selectivity and single function. Herein, we designed a theranostic strategy based on the fluorescence resonance energy transfer (FRET) mechanism. The theranostic prodrug was constructed with an anticancer drug camptothecin (CPT), a cleavable linker based on disulfide bonds (SS) and a fluorophore naphthalimide derivative (NAP). For this drug delivery and reporting system (NAP-SS-CPT), FRET occurs between CPT (energy donor) and NAP (energy receptor); and upon cellular uptake by GSH-overexpressing cancer cells, disulfide bonds could be successfully cleaved by the high concentration of GSH, and FRET process was interrupted to achieve dual fluorescence response and specifically release of CPT. The drug delivery system features some favorable properties, like excellent pH-stability, high selectivity and cytotoxicity towards GSH-overexpressing cells and relatively lower cytotoxicity towards normal cells. Fluorescence analysis reveals that NAP-SS-CPT shows a ratiometric fluorescence signal under excitation at 400 nm for quantitative detection of GSH. Intracellular fluorescence imaging studies indicate that the prodrug can be efficiently internalized in HeLa cells and used for real-time monitoring of drug release. Moreover, MTT and flow cytometry assay indicate that NAP-SS-CPT exhibits high pro-apoptotic effect for cancer cells. This strategy may provide a new approach for cancer diagnosis and therapy.

An AIE-based fluorescent test strip (OPD-TPE-Py-2CN) for rapid and sensitive detection of gaseous phosgene was designed. The fluorescence changes from blue to green upon exposure to phosgene. And the detection limit (1.87 ppm) is lower than the "harmless" level of human response to acute phosgene exposure.

The rational design of effective tools capable of monitoring hydrogen sulfide (H2S) is of great importance to fully understand its physiological and pathological functions. Herein, a self-assembled fluorescent nanoprobe with both aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) characteristics for H2S detection has been successfully developed via a modified nanoprecipitation method. The nanoprobe features high water dispersibility, a large Stokes shift (ca. 100 nm), good biocompatibility as well as high selectivity towards H2S over other putative interferents. Live cell imaging experiments demonstrate that the nanoprobe, with good cell-membrane permeability, can facilitate the visualization of exogenous and endogenous H2S levels. Moreover, the nanoprobe has also been found capable of detecting H2S in zebrafish. This nanoprobe with AIE and ESIPT characteristics can provide a novel method for the development of fluorescent probes for monitoring biological processes.

Alpha-L-fucosidase (AFU) plays vital roles in some physiological processes that closely relate to several diseases. Herein, a ratiometric fluorescent probe for the alpha-L-fucosidase (AFU) assay based on a single fluorophore has been developed by functionalizing a new fluorophore platform (6-bromo-anthracenecarboximide) with an α-L-fucose group. AFU cleaves the α-L-fucose group from the probe molecule and remarkably alters its photophysical properties, thus realizing ratiometric detection of AFU. Due to the specificity and high efficiency of the enzymatic reaction, this probe can sensitively and selectively detect AFU in aqueous media and biological milieus with a detection limit of 0.0033 U mL−1. Moreover, the probe can be employed to monitor and spatially map endogenous AFU levels in a hepatocellular carcinoma (HCC) model of zebrafish. Hence, the probe holds significant promise for conducting pathological research on AFU-involved diseases.

Bioorthogonal "bond cleavage" reactions hold great promise in a variety of biological applications such as controlled activation of the drug and probe, while the application of these biocompatible reactions in living animals is still in its infancy and has yet to be further explored. Herein we demonstrate a nanosized and two-component bioorthogonal system for tumor inhibition through the combined action of chemo- and photothermal therapy. The trigger of the system was fabricated by immobilizing PEGylated tetrazine on the gold nanorods, and the bioorthogonal prodrug was synthesized by caging the drug camptothecin with vinyl ether, followed by encapsulating it with phospholipid liposomes. The tetrazine-based trigger effectively mediates the bioorthogonal reaction and triggers the release of camptothecin for chemotherapy, and the gold nanorods exhibit high photothermal capability for photothermal therapy and for three-dimensional optoacoustic imaging. Upon injection into tumor-bearing mice, the two components accumulate in the tumor region and carry out a bioorthogonal reaction therein, hence releasing the parent drug. The combined actions of chemo- and photothermal therapy greatly inhibited tumor growth in mice. This strategy may afford a promising approach for achieving controlled release of an active drug in vivo through an alternative external stimulus-a bioorthogonal reaction.

A fluorescent probe based on a triphenylamine benzopyridine platform for hydrogen sulfide (H2S) assaying has been designed and synthesized. As a result of the H2S-triggered cleavage reaction, the disappearance of the quenching effect of dinitrophenyl and the increased hydrophobicity in a poor solvent lead to the aggregation-induced emission (AIE) effect; consequently an obvious 'turn-on' fluorescence signal can be observed in this process. The probe TPANF features high selectivity towards H2S, low detection limit (0.17 μM), and good photostability and biocompatibility. Moreover, it has been successfully utilized to monitor H2S in food samples to distinguish the extent of food deterioration and to identify the H2S concentration variation in living cells. In addition, endogenous H2S in HCT-116 xenograft tumor tissues was imaged by using this probe. The approach could provide useful insight for the development of other activatable AIE-based probes that are potentially helpful for specific assaying in food chemistry and biological systems.

Three kinds of nickel-loaded anhydrous calcium silicate nanocatalysts (ACS), including Ni-ACS-Dop, Ni-ACS-Iex and Ni-ACS-Im, were prepared by introducing Ni species through doping in the synthesis of calcium silicate hydrate (CSH) nanosheets, ion-exchange with premade CSH nanosheets and deposition on calcined ACS nanosheets, respectively. Although Ni species were introduced in different ways, all the Ni-ACS catalysts showed similar chemical compositions and microstructures, where Ni nanoparticles were highly dispersed on the ultrathin ACS nanosheets with a large surface area and good thermal stability. However, the differences in the way of Ni introduction did produce Ni with different electronic states. The Ni-ACS-Iex catalyst with "surface Ni" as a dominant form had more electrons enriched on the surface of Ni, which led to the highest activity in the dry reforming of methane (DRM) reaction among the three catalysts, whereas the Ni-ACS-Dop catalyst with "lattice Ni" as a dominant form showed an electron-deficient property and lowest activity. Different from the introduction of a more favourable nanostructure or chemical component to the catalyst system, this work controlled the chemical environment of metal precursors and created metal catalysts with a preferred surface electronic state during synthesis, which could be a new strategy to improve the catalytic activity.

Dihydroberberine (DHB), a hydrogenated derivative of berberine (BBR), has been firstly identified in Phellodendri Chinese Cortex (PC) by HPLC-ESI-MS/MS. Nowadays most researches on PC focus on its main components like BBR, however, the role of its naturally-occurring derivatives remains poorly defined heretofore. The present work aimed to comparatively evaluate the in vivo anti-inflammatory properties and mechanisms of DHB and BBR in three typical inflammatory murine models. The results showed that DHB effectively mitigated acetic acid-induced vascular permeability, xylene-elicited ear edema and carrageenan-caused paw edema. Meanwhile, DHB markedly attenuated the inflammatory cell infiltration in pathological sections of ears and paws. DHB was also observed to significantly decrease the production and mRNA expression levels of IL-6, IL-1β, TNF-α, NO (iNOS) and PGE2 (COX-2), increase the release of IL-10, and inhibit the activation of NF-κB and MAPK signaling pathways. The anti-inflammatory effect of DHB was weaker than that of BBR. The results might further contribute to unraveling the pharmacodynamic basis of PC and support its ethnomedical use in the treatment of inflammatory diseases. DHB possesses good potential to be further developed into a promising anti-inflammatory alternative, and can serve as a lead template for novel anti-inflammatory candidate.