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Qiang-qiang Fan,1 Bing-tao Zhai,1 Dan Zhang,1 Xiao-fei Zhang,1 Jiang-xue Cheng,1 Dong-yan Guo,1– 3 Huan Tian4 1School of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 2Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 3State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 4Xi’an Hospital of Traditional Chinese Medicine, Xi’an, 712046, People’s Republic of ChinaCorrespondence: Dong-yan Guo; Huan Tian, Email 2051080@sntcm.edu.cn; 18149412681@163.comPurpose: Yinhua Gout Granules (YGG) is a traditional Chinese medicine preparation with a variety of pharmacological effects, and its clinical efficacy in the treatment of gouty arthritis (GA) has been fully confirmed. However, the pharmacodynamic basis of YGG and its anti-inflammatory mechanism of action in GA are unknown. The objective of this study was to identify the active components and molecular mechanisms of YGG in the treatment of GA.Methods: Ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) and network pharmacology were used to identify and predict the potential active ingredients and related signaling pathways. Then, we revealed the anti-GA effects of YGG based on pharmacodynamic experiments in GA rats. Finally, we integrated transcriptomics and network pharmacology to elucidate the potential mechanism of action and verified the putative mechanism by molecular docking, immunohistochemical (IHC) and Western blot.Results: We have identified 10 major active components of YGG that may have anti-GA effects, such as ferulic acid, rutin, luteolin, etc. Using molecular docking, we found that 10 major compounds could bind well to TNF, PTGS2, IL-6, IL1β, NOS2 and PTGS1, and the binding energies were all less than − 5 kcal/mol. Animal studies have shown that YGG can improve joint inflammation and inflammatory cell infiltration, reduce serum UA, BUN and Cr levels (p

Background: To evaluate the long-term efficacy of single-balloon enteroscopy endoscopic retrograde cholangiography (SBE-ERC) for the treatment of biliary obstruction and to analyze the factors affecting the recurrence of benign bilioenteric anastomotic stricture after SBE-ERC treatment., Methods: The clinical data of patients with biliary diseases treated with SBE-ERC after choledochojejunostomy in our hospital from January 2015 to December 2021 were analyzed retrospectively for the success rates of diagnosis and treatment and the incidence of complications. Patients who were diagnosed with benign bilioenteric anastomotic stricture were followed up. The independent factors affecting recurrence were obtained by univariate and multivariate analyses using the Kaplan‒Meier method and Cox proportional hazard regression model., Results: A total of 289 SBE-ERCs were performed in 165 patients. The overall success rate was 83.0% (240/289). The incidence of postoperative complications was 5.2% (15/289). The 108 successfully treated patients diagnosed with benign bilioenteric anastomotic stricture were followed up. Twenty-six percent (29/108) of patients had recurrent stricture after SBE-ERC. The biliary patency rates at 1 year, 2 years and 5 years after SBE-ERC were 90.1%, 69.3%, and 53.9%, respectively. Single-factor analysis revealed the absence of intrahepatic biliary gas imaging during endoscopy ( χ 2 =5.366, P = 0.021), a diameter of balloon dilatation during the last endoscopic treatment less than 0.8 cm ( χ 2 =4.552, P = 0.033), and the presence of a thread in the anastomosis ( χ 2 =8.921, P = 0.003) as risk factors for recurrence. A non-indwelling biliary plastic stent ( χ 2 =14.868, P < 0.001) and undergoing only one ERCP treatment ( χ 2 =13.313, P = 0.001) were risk factors for the recurrence of benign stricture after SBE-ERC resection. Multivariate analysis revealed that the absence of a stent (HR = 0.15, 95% CI 0.06-0.40, P = 0.001), absence of intrahepatic biliary gas imaging during endoscopy (HR = 0.39, 95% CI 0.17-0.91, P = 0.03) and the presence of a thread in the anastomosis (HR = 3.69, 95% CI 1.59-8.57, P = 0.002) were independent risk factors for stricture recurrence., Conclusions: Treating biliary disease after choledochojejunostomy with SBE-ERC is safe and effective, with a good immediate technical success rate and an acceptable incidence of complications. SBE-ERC has long-term efficacy in the treatment of benign bilioenteric anastomotic stricture. The absence of intrahepatic biliary gas imaging during endoscopy, non-indwelling biliary stents and the existence of anastomotic threads are independent risk factors for the recurrence of benign bilioenteric anastomotic stricture., (© 2024. The Author(s).)

Objective: In this study, we examined the effectiveness of hyperbaric oxygen (HBO) therapy in ameliorating cognitive deficits in mice with Alzheimer's disease (AD), while also assessing its impact on the autophagic pathway within the context of AD., Methods: 20 double-transgenic mice expressing the amyloid precursor protein and presenilin 1 (APP/PS1) were purposefully selected and randomly assigned to groups A and B. Concurrently, 20 C57BL/6 mice were chosen and randomly categorized into groups C and D, each consisting of 10 mice. Mice in groups B and D received HBO treatment. The Morris water maze assay was used to assess changes in mouse behavior. Immunohistochemistry techniques were used to quantify the expression levels of amyloid-beta 42 (Aβ42) and microtubule-associated protein 1A/1B-light chain 3 (LC3) in hippocampal tissues, while western blot analysis was used to investigate the levels of LC3-II, p62, phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) proteins within hippocampal tissues., Results: Mice allocated to group B exhibited reduced escape latency and prolonged dwell time in the target quadrant compared to other groups. Histological examination revealed conspicuous plaque-like deposits of Aβ42 in the hippocampal tissues of mice in groups A and B. Group B displayed diminished Aβ42-positive reactants and augmented microtubule-associated protein 1A/1B-LC3-positive reactants compared to group A. LC3-positive reactants were also detected in the hippocampal tissues of mice in groups C and D, surpassing the levels observed in groups A and B. Furthermore, group B demonstrated significantly lower expression of mTOR protein and markedly higher expression of LC3-II protein in mouse hippocampal tissues when compared to group A ( P < 0.05). Conversely, there were no significant disparities noted in PI3K and p62 protein expression between groups B and A. Notably, no discernible discrepancies were observed in the expression levels of mTOR, PI3K, LC3-II, and p62 proteins between groups C and D within mouse hippocampal tissues., Conclusion: HBO treatment demonstrates efficacy in enhancing cognitive function in mice with AD and holds promise as a potential therapeutic intervention for AD by facilitating the activation of the mTOR pathway-mediated autophagy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fan, Chen, Fu, Li, Zeng, Bian, Li and Song.)

Ethnopharmacological Relevance: Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown., Aim of the Study: The aim of this study was to elucidate the possible cardiotoxic symptoms caused by high-doses of HCSc and to further reveal the complex mechanisms by which it causes cardiotoxicity., Materials and Methods: UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and sub-acute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot., Results: We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage, while low-dose of HCSc had no such changes. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1β, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway., Conclusions: In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of possible cardiotoxicity induced by high-dose HCSc. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors in the contemporary era, representing a significant global health concern. Early HCC patients have mild symptoms or are asymptomatic, which promotes the onset and progression of the disease. Moreover, advanced HCC is insensitive to chemotherapy, making traditional clinical treatment unable to block cancer development. Sorafenib (SFB) is a first-line targeted drug for advanced HCC patients with anti-angiogenesis and anti-tumor cell proliferation effects. However, the efficacy of SFB is constrained by its off-target distribution, rapid metabolism, and multi-drug resistance. In recent years, nanoparticles based on a variety of materials have been demonstrated to enhance the targeting and therapeutic efficacy of SFB against HCC. Concurrently, the advent of joint drug delivery systems has furnished crucial empirical evidence for reversing SFB resistance. This review will summarize the application of nanotechnology in the field of HCC treatment over the past five years. It will focus on the research progress of SFB delivery systems combined with multiple therapeutic modalities in HCC treatment., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Gastric cancer (GC) is one of the most malignant tumors with high morbidity and mortality in the world. Compound a2 , a Jiyuan oridonin derivative, exhibited excellent anti-proliferative activity against GC cells. To investigate the gastric cellular response to a2 therapy as a novel drug candidate, we adopted a pseudotargeted metabolomics method to explore metabolic variation in a2 -induced MGC-803 gastric cells using liquid chromatography tandem mass spectrometry combined with multivariate statistical analysis. The results showed that a2 treatment induced significant metabolic changes in the levels of aminoacyl-tRNA biosynthesis, alanine, aspartate and glutamate metabolism, pyrimidine metabolism, and tricarboxylic acid cycle, approximately 80% of the metabolites were down-regulated in the low-dose and high-dose groups including aspartate, tryptophan, sedoheptulose 7-phosphate, succinate, 2'-deoxyadenosine, uridine, cytidine, etc. which can provide evidence for a new therapy of GC., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To explore the effects of trunk training using motor imagery on trunk control and balance function in patients with stroke., Methods: One hundred eligible stroke patients were randomly divided into a control group and trial group. The control group was given routine rehabilitation therapy, while the trial group was given routine rehabilitation therapy and trunk training using motor imagery., Results: Prior to treatment, there was no significant difference between the two groups (P > 0.05) in Sheikh's trunk control ability, Berg rating scale (BBS), Fugl-Meyer assessment (FMA), movement length, movement area, average front-rear movement speed, average left-right movement speed, and surface electromyography (sEMG) signal of the bilateral erector spinae and rectus abdominis. After treatment, Sheikh's trunk control ability, FMA, and BBS in the two groups were significantly higher than those before treatment (P < 0.05). The movement length, movement area, the average front-rear movement speed, and the average left-right movement speed in the two groups decreased significantly (P < 0.05). The differences of these indicators between the two groups were statistically significant (P < 0.05). After treatment, the rectus abdominis and erector spinae on the affected side of the two groups improved when compared with those before treatment (P < 0.05). The rectus abdominis and erector spinae on the healthy side of the trial group descended after treatment (P < 0.05), while little changes were observed on the healthy side of the control group after treatment (P > 0.05). The rectus abdominis and erector spinae on the affected side of the trial group improved when compared with those in the control group (P < 0.05). There was no significant difference between the two groups in the decline of abdominalis rectus and erector spinal muscle on the healthy side., Conclusion: Trunk training using motor imagery can significantly improve the trunk control ability and balance function of stroke patients and is conducive to promoting the recovery of motor function., (© 2023. The Author(s).)

Highly efficient charge transfer is a critical factor to modulate the photocatalytic activity. However, the conscious modulation of charge transfer efficiency is still a great challenge. Herein, a novel interfacial Mo-N bond and appropriate oxygen vacancies (OVs) modulated S-scheme MoO 3-x /S-CN heterojunction was rationally fabricated for efficient photocatalytic disinfection. The results of characterizations and density functional theory (DFT) calculations suggested that the enhanced charge transfer dynamics is ascribed to the optimizing oxygen vacancies density and forming interfacial Mo-N bond. It can improve charge transfer efficiency from 36.4% (MoO 3-x ) to 52.5% (MoO 3-x /S-CN) and produce more reactive oxygen species (ROS), achieving entirely inactivate of 7.60-log E. coli and S. aureus within 50 min and 75 min. Besides, MoO 3-x /S-CN can well resist the disturbance from the coexisting substances, and can be applied in a wide pH range, and even authentic water bodies. Monitoring of bacterial antioxidant systems and membrane integrity revealed that bacterial inactivation begins with the oxidation of cell membrane and dies from leakage of intracellular substances and destruction of cell structure. This work provides an inspiration on consciously modulating S-scheme charge transfer efficiency by optimizing oxygen vacancies density and atomic-level interface control for promoting the photocatalytic antibacterial activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Pancreatic fistula (PF) is the main complication in patients undergoing pancreaticoduodenectomy. Computed tomography (CT) value can reflect pancreatic tissue characteristics which is related to PF. This study was designed to study the relationship between the preoperative CT value and pancreatic fistula., Methods: We retrospectively reviewed the clinical and medical data of patients undergoing pancreaticoduodenectomy from 2017 to 2021. The pancreatic CT value and the CT value ratios of the pancreas and abdominal aorta (P CT /A CT ) were measured and compared between the PF group and non-PF group. The values in different PF severity groups were compared using variance analysis. A cut-off value was selected by receiver operating characteristic (ROC) curve. Single-factor and multiple-factor analysis were performed to evaluate Correlation between PF and CT., Results: One hundred and twenty-seven cases were included in this study. The P CT /A CT in the PF group was significantly lower than that in the non-PF group (P<0.001), and the P CT /A CT value was correlatively lower in the severe PF group than in the mild PF group (P=0.008). A cutoff value of 0.99 was selected by ROC curves analysis. Further multifactor analysis identified P CT /A CT <0.99 to be an independent preoperative predictor [odds ratio (OR): 11.3, P<0.01]., Conclusions: The preoperative pancreatic CT value can indirectly reflect the histological condition of the pancreas and thus may related to postoperative PF after pancreaticoduodenectomy and provide useful information for surgeons in deciding upon the pancreaticojejunostomy method., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-19/coif). The authors have no conflicts of interest to declare., (2023 Gland Surgery. All rights reserved.)

Microbial electrolysis cells (MECs) have rapidly developed into a promising technology to treat sulfate-rich wastewater that lacks electron donors. Hence, a better understanding of the effect on the microbial community structure caused by different sources in bioelectrochemical systems is required. This study sought to investigate the effect of different carbon sources (NaHCO 3 , ethanol, and acetate were employed as sole carbon source respectively) on the performance of sulfate-reducing biocathodes. The sulfate reduction efficiency enhanced by the bioelectrochemical systems was 8.09 - 11.57% higher than that of open-circuit reference experiments. Furthermore, the optimum carbon source was ethanol with a maximum sulfate reduction rate of 170 mg L -1 d -1 in the bioelectrochemical systems. The different carbon sources induced significant differences in sulfate reduction efficiency as demonstrated by the application of a micro-electrical field. Microbial community structure and network analysis revealed that all three kinds of carbon source systems enriched large proportions of sulfate-reducing bacteria and electroactive bacteria but were significantly distinct in composition. The dominant sulfate-reducing bacteria that use NaHCO 3 and acetate as carbon sources were Desulfobacter and Desulfobulbus, whereas those that use ethanol as carbon source were Desulfomicrobium and Desulfovibrio. Our results suggest that ethanol is a more suitable carbon source for sulfate reduction in bioelectrochemical systems., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study used the zebrafish model to explore the hepatotoxicity of Rhododendri Mollis Flos(RMF). The mortality was calculated according to the number of the survival of zebrafish larvae 4 days after fertilization under different concentration of RMF, and the dose-toxicity curve was fitted to preliminarily evaluate the toxicity of RMF. The liver phenotypes under the sublethal concentration of RMF in the treatment group and the blank control group were observed by hematoxylin-eosin(HE) staining and acridine orange(AO) staining. Meanwhile, the activities of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were determined to confirm the hepatotoxicity of RMF. Real-time quantitative polymerase chain reaction(real-time PCR) and Western blot were used to determine the expressions of genes and proteins in zebrafish larvae. Gas chromatography time-of-flight mass spectrometry(GC-TOF-MS) was used to conduct untargeted metabolomics testing to explore the mechanism. The results showed that the toxicity of RMF to zebrafish larvae was dose-dependent, with 1 100 μg·mL~(-1) of the absolute lethal concentration and 448 μg·mL~(-1) of sublethal concentration. The hepatocyte apoptosis and degeneration appeared in the zebrafish larvae under the sublethal concentration of RMF. The content of ALT and AST in zebrafish larvae at the end of the experiment was significantly increased in a dose-dependent manner. Under the sublethal concentration, the expressions of genes and proteins related to apoptosis in zebrafish larvae were significantly increased as compared with the blank control group. The results of untargeted metabolomics showed that the important metabolites related to the he-patotoxicity of RMF were mainly enriched in alanine, aspartic acid, glutamic acid, and other pathways. In conclusion, it is inferred that RMF has certain hepatotoxicity to zebrafish larvae, and its mechanism may be related to apoptosis.

Developing photocatalysts with superior performance to generate hydrogen peroxide (H 2 O 2 ) and degrade oxytetracycline (OTC) is an effective strategy for the treatment of energy crisis and water purification. Herein, BN nanosheets were anchored onto the Zn 3 In 2 S 6 microspheres for the research. Experimental and density functional theory (DFT) results demonstrate that due to different work functions and unique 2D/2D contact, the electron is spatially separated in BN/Zn 3 In 2 S 6 nanocomposite, which increases the electron transfer efficiency from 43.7% (Zn 3 In 2 S 6 ) to 55.6% (BN/ZIS-4). As a result, BN/ZIS-4 with optimal ratio of BN and Zn 3 In 2 S 6 exhibits the highest OTC degradation efficiency (84.5%) and H 2 O 2 generation rate (115.5 μmol L -1 ) under visible light illumination, which is 2.2 and 2.9 times than that of pristine Zn 3 In 2 S 6 . H 2 O 2 generation is dominated by two pathways: two-step single-electron process (O 2 → ∙O 2 - → H 2 O 2 ) and another way (O 2 → ∙O 2 - → 1 O 2 → H 2 O 2 ). In the process of degrading OTC, ∙O 2 - , 1 O 2 and ∙OH are regarded as the main active species. This work offers a new insight for designing efficient, stable and reusable photocatalysts to solve current environmental conundrums., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study aims to evaluate the anti-tumor and analgesic activities of Compound Kushen Injection(CKI) based on zebrafish model in vivo and investigate the anti-tumor mechanism. To be specific, zebrafish tumor xenotransplantation model was established by microinjection of murine LPC H12 cells into yolk sac. Then the high-dose CKI(H-CKI), medium-dose CKI(M-CKI), low-dose CKI(L-CKI) groups, and the model group were set. The anti-tumor activity of CKI was evaluated with the tumor area growth fold and integral absorbance(IA) growth fold 72 h after administration. The peripheral pain and central pain in zebrafish were respectively induced with acetic acid(AA) and phorbol myristate acetate(PMA). Zebralab ViewPoint system was employed to monitor behavioral trajectory of zebrafish, and movement times, movement time, movement distance, and movement velocity were used to evaluate the analgesic activity of CKI. Finally, real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) was performed to detect the expression levels of apoptosis-related B lymphocyte tumor-2(Bcl-2) and phosphatidylinositol-3-kinase(PI3 K)/protein kinase B(Akt or PKB) pathway-related genes, for the verification of the anti-tumor mechanism. Compared with the model group, M-CKI and H-CKI significantly reduced the growth folds of tumor area and IA, relief the peripheral pain and central pain. The mechanism was that CKI can up-regulate the expression of cysteine aspartic acid specific protease-3(caspase-3, Casp3) and caspase-9(Casp9), down-regulate the expression of phosphoinositide 3-kinase(PI3 K) and Akt, and significantly reduce the expression of Bcl-2, hypoxia-inducible factor-1α(HIF-1α), and vascular endothelial growth factor(VEGF). In conclusion, CKI has significant inhibitory effect on tumor growth and pain, which is related to the PI3 K/Akt signaling pathway. The pathway mediates cell apoptosis, suppresses tumor growth, and alleviates tumor pain.

Wheat is one of the most important food crops in the world, with development of the grains directly determining yield and quality. Understanding grain development and the underlying regulatory mechanisms is therefore essential in improving the yield and quality of wheat. In this study, the developmental characteristics of the pericarp was examined in developing wheat grains of the new variety Jimai 70. As a result, pericarp thickness was found to be thinnest in grains at the top of the spike, followed by those in the middle and thickest at the bottom. Moreover, this difference corresponded to the number of cell layers in the pericarp, which decreased as a result of programmed cell death (PCD). A number of autophagy-related genes ( ATGs ) are involved in the process of PCD in the pericarp, and in this study, an increase in ATG8-PE expression was observed followed by the appearance of autophagy structures. Meanwhile, following interference of the key autophagy gene ATG8 , PCD was inhibited and the thickness of the pericarp increased, resulting in small premature grains. These findings suggest that autophagy and PCD coexist in the pericarp during early development of wheat grains, with both processes increasing from the bottom to the top of the spike. Moreover, PCD was also found to rely on ATG8 -mediated autophagy. The results of this study therefore provide a theoretical basis for in-depth studies of the regulatory mechanisms of wheat grain development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Yan, Cui, Huang, Sui, Guo, Fan and Chu.)

Ethnopharmacological Relevance: Curcumae Rhizoma-Sparganii Rhizoma (CR-SR), an ancient and classical herbal couple, has been extensively used for tumor treatment in clinic of traditional Chinese medicines (TCMs)., Aim of the Study: The study aimed to uncover the anti-tumor active materials of CR-SR water decoction (CR:SR = 1:1) via an integrated approach of spectrum-effect relationship, molecular docking, and ADME evaluation., Materials and Methods: The anti-tumor activities toward A549, HepG2, Hela, BGC-823, and MCF-7 cells of the different polar elution fractions (DPEFs) of CR, SR, and CR-SR were determined by Cell Counting Kit-8 (CCK-8) assay. Likewise, the DPEFs' combinations of CR and SR were also tested. The chemical fingerprints of these fractions were profiled by HPLC. Meanwhile, HPLC-ESI-Q-TOF-MS/MS was applied for the identification of chemical components. The main effect-related compounds were screened out by spectrum-effect relationship and molecular docking method. The oral bioavailability and druggability of these active components were subsequently evaluated. Finally, five monomeric compounds were validated experimentally using HepG2 cells., Results: The 80% ethanol elution fraction of CR, SR, and CR-SR showed strong anti-tumor effects toward five cells. Also, the combinations with the 80% ethanol elution fraction of CR and SR showed stronger tumor inhibition effects among the DPEFs' combinations of CR and SR. By spectrum-effect relationship, HPLC-MS, and molecular docking analysis, 24 main effect-related compounds seemed to have potential anti-tumor effects. ADME evaluation showed rutin performed low oral bioavailability and druggability. Therefore, we suppose that 23 compounds (including 4 unknown compounds) are the primary anti-tumor active components of CR-SR water decoction. Among them, zederone, curcumol, chlorogenic acid, calycosin, and curcumenol were validated successfully with good tumor inhibition effects., Conclusions: In summary, this study demonstrated that the multi-components of CR-SR contribute to its anti-tumor effects. It established a rapid and useful strategy to explore the active material basis of traditional Chinese herbal couples with a multi-technology integrated approach in practice, including chromatography, mass spectrometry, machine algorithm models, online databases, and in vitro cell experiments., (Copyright © 2021. Published by Elsevier B.V.)

Photocatalysis is considered to be an effective way to remove organic pollutants, but the key to photocatalysis is finding a high-efficiency and stable photocatalyst. 2D materials-based heterojunction has aroused widespread concerns in photocatalysis because of its merits in more active sites, adjustable band gaps and shorter charge transfer distance. Among various 2D heterojunction systems, 2D/2D heterojunction with a face-to-face contact interface is regarded as a highly promising photocatalyst. Due to the strong coupling interface in 2D/2D heterojunction, the separation and migration of photoexcited electron-hole pairs are facilitated, which enhances the photocatalytic performance. Thus, the design of 2D/2D heterojunction can become a potential model for expanding the application of photocatalysis in the removal of organic pollutants. Herein, in this review, we first summarize the fundamental principles, classification, and strategies for elevating photocatalytic performance. Then, the synthesis and application of the 2D/2D heterojunction system for the removal of organic pollutants are discussed. Finally, the challenges and perspectives in 2D/2D heterojunction photocatalysts and their application for removing organic pollutants are presented., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alcoholic liver disease (ALD) is a major health issue globally due to the consumption of alcoholic beverages. Thymus quinquecostatus Celak is a food additive and an edible herb that is widely used in Asia and possesses hepatoprotective activity, but the underlying mechanisms behind this protective activity are not completely understood. The purpose of this study was to investigate the hepatoprotective effects of Thymus quinquecostatus Celak extract (TQE) against ALD as well as the underlying mechanism based on gut microbiota and the gut-liver axis. TQE supplementation markedly alleviated chronic alcohol-induced liver injury in C57 mice. TQE also ameliorated gut barrier dysfunction induced by alcohol. Consequently, the activation of the lipopolysaccharide (LPS) translocation-mediated TLR4 pathway and the subsequent inflammatory response and ROS overproduction in the liver were suppressed. Meanwhile, alcohol-induced gut microbiota dysbiosis was also corrected by TQE. To further investigate the contribution of gut dysbiosis correction to the beneficial effects of TQE on ALD, a fecal microbiota transplantation study was conducted. TQE-manipulated gut microbiota transplantation markedly counteracted the alcohol-induced gut dysbiosis in the recipient mice. In parallel with gut dysbiosis correction, liver damage was partly ameliorated in the recipient mice. Gut barrier dysfunction, endotoxemia, TLR4 pathway induction as well as downstream inflammatory response and ROS overproduction were also partly suppressed due to gut dysbiosis correction in alcohol-fed recipient mice. In summary, these results suggest that gut dysbiosis correction contributes to the hepatoprotective effects of TQE against alcohol through the gut-liver axis.

A mild, efficient and eco-friendly method for the oxidation of 1-Bn-DHIQs to 1-Bz-DHIQs without concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs is very important for the syntheses of 1-Bz-DHIQ alkaloids and analogues. In this article, we developed a novel Cu(ii)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp 3 )-H bonds adjacent to the C-1 positions of various 1-Bn-DHIQs. It was observed that when 0.2 equiv. of Cu(OAc) 2 ·2H 2 O was used as the catalyst, 3.0 equiv. of AcOH was used as the additive and air (O 2 ) was used as a clean oxidant, various 1-Bn-DHIQs could be efficiently oxidized to corresponding 1-Bz-DHIQs at 25 °C in DMSO. Especially, almost no concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs was observed during the above reaction. In addition, this method was successfully applied in the first total synthesis of the alkaloid canelillinoxine., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients., (© 2021 The Authors.)

Background: Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section. This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients., Methods: In this double-blinded, randomized controlled clinical trial, parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion (0.05 μg·kg-1·min-1) just before spinal anesthesia continuing for 30 min or ephedrine bolus (0.15 mg/kg) just before spinal anesthesia. A rescue bolus (5 μg norepinephrine for the norepinephrine group, and 5 mg ephedrine for the ephedrine group) was administered whenever hypotension occurred. Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration. Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block, and neonatal cerebral oxygenation 10 min after birth., Results: In total, 190 patients were enrolled; of these patients, 177 were included in the final analysis. Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group (29.5% vs. 44.9%, odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.28-0.95, P = 0.034). Moreover, the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group (OR: 0.22, 95% CI: 0.11-0.44, P < 0.001), and patients suffered less nausea and vomiting (OR: 0.28, 95% CI: 0.11-0.70, P = 0.004). There was no difference in Apgar scores and umbilical arterial blood gas analysis between the two groups. However, neonatal cerebral regional saturations were significantly higher after birth in the norepinephrine group than in the ephedrine group (mean difference: 2.0%, 95% CI: 0.55%-3.45%, P = 0.008)., Conclusion: In patients undergoing elective cesarean section with spinal anesthesia, norepinephrine infusion compared to ephedrine bolus resulted in less hypotension and tachycardia, and exhibited potential neonatal benefits., Trial Registration: ClinicalTrials.gov, NCT02542748; https://clinicaltrials.gov/ct2/show/record/NCT02542748., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Aim: To implement the nursing rounds to improve the quality and patient satisfaction of the outpatient department., Background: Patient satisfaction is one of the most critical standards for judging the quality of hospitals. Clinical daily nursing rounds significantly increase patient satisfaction and influence safety., Method: SQUIRE guidelines directed the execution of a quality improvement project, which used the Driver Model to improve patient satisfaction in a Chinese outpatient department with 15,000 visits per day (4 million/year). Patient satisfaction based on questionnaires (1,541), pre-intervention and (1,219) post-intervention provided increased satisfaction (p < .05)., Results: Improvements validated were satisfaction with outpatient services from patients, effective nurse-patient communications, an increase in the quality of nursing care, doctors' satisfaction with the outpatient department operations, reduced wait time and more efficient management, all impact safety., Conclusions: The institution of daily nursing rounds made an overall improvement in the operations of the outpatient department, which increased patient satisfaction, quality of care and safety., Implications for Nursing Management: Nursing rounds promote patient satisfaction through assessment of operations, addressing patient and staff needs, and appropriate interventions to rectify issues and reduce adverse outcomes. Patient satisfaction impacts quality, outcomes and safety in clinical settings., (© 2020 John Wiley & Sons Ltd.)

Objective: To analyze the effective components of Chinese medicine (CM) contained in Chaihu Shugan Powder (, CSP) in the treatment of depressive disorders and to predict its anti-depressant mechanism by network pharmacology., Methods: Absorption, distribution, metabolism, excretion, and toxicity calculation method was used to screen the active components of CSP. Traditional Chinese Medicine System Pharmacological Database Analysis Platform and text mining tool (GoPuMed database) were used to predict and screen the active ingredients of CSP and anti-depressive targets. Through Genetic Association Database, Therapeutic Target Database, and PharmGkb database targets for depression were obtained. Cytoscape3.2.1 software was used to establish a network map of the active ingredients-targets of CSP, and to analyze gene function and metabolic pathways through Database for Annotation, Visualization and Integrated Discovery and the Omicshare database., Results: The 121 active ingredients and 15 depression-related targets which were screened from the database can exert antidepressant effects by improving the neural plasticity, growth, transfer condition and gene expression of neuronal cell, and the raise of the expression of gap junction protein. The 15 targets passed 14 metabolic pathways, mainly involved in the regulation of neurotransmitters (5-hydroxytryptamine, dopamine and epinephrine), inflammatory mediator regulation of TRP channels, calcium signaling pathway, cyclic adenosine monophosphate signaling pathway and neuroactive ligand-receptor interaction and other signal channels to exert anti-depressant effects., Conclusion: This article reveals the possible mechanism of CSP in the treatment of depression through network pharmacology research, and lays a foundation for further target studies.

Backgrounds: Although kidney impairments have been reported following immune checkpoint inhibitors (ICIs) in clinical studies, there are few pharmacoepidemiology studies to compare the occurrences, clinical features, and prognosis of renal adverse effects., Methods: Disproportionality and Bayesian analysis were used in data mining to screen the suspected renal adverse effects after the administration of different ICIs, based on FDA's Adverse Event Reporting System (FAERS) from January 2004 to September 2019. The time to onset, fatality and hospitalization rates of renal adverse effects were also investigated., Results: We identified 1444 reports of renal adverse effects. Affected patients tended to be older than 65 years (52.7%). Renal effects were most commonly reported in nivolumab monotherapy (33.24%). Atezolizumab appeared the strongest association among six ICI monotherapies, based on the highest reporting odds ratio (ROR = 144.38, two-sided 95% CI = 123.08 -169.37), proportional reporting ratio (PRR = 139.13, χ 2  = 21 425.38), and empirical Bayes geometric mean (EBGM = 131.75, one-sided 95% CI = 115.28). The combination treatments showed higher RORs, PRRs, and EBGMs, compared with either nivolumab or pembrolizumab monotherapy. The median onset time of renal adverse effects was 48 (interquartile range [IQR] 18.75-121.25) days after the monotherapies of ICI regimens. Patients treated with the combination of nivolumab plus ipilimumab were younger than receivers in nivolumab monotherapy (63.81 ± 12.03 vs 66.39 ± 11.53, P = .004); The fatality rate of renal adverse effects appeared lower in the combination group, compared to nivolumab monotherapy (18.53% vs 27.50%, P = .004). The top hospitalization rates due to renal effects occurred in patients with combination therapies., Conclusion: Based on the FAERS database, we profiled renal adverse effects after various ICIs with real-world data in occurrences, clinical characteristics, and prognosis. Renal effects should be tightly monitored, especially within the first several months after ICIs administration. Particular concern should be paid for patients with a tendency for kidney impairments, such as old age., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

LSD1 (histone lysine specific demethylase 1) takes part in the physiological process of cell differentiation, EMT (epithelial-mesenchymal transition) and immune response. In this study, we found LSD1 expression in metastatic gastric cancer tissues was significantly higher than that in normal tissues. Furthermore, LSD1 deletion was found to suppress gastric cancer migration by decreasing intracellular miR-142-5p, which further led to the upregulation of migration suppressor CD9, a newly identified target of miR-142-5p. While LSD1 was reported as a demethylase of H3K4me1/2, H3K9me1/2 and several non-histone proteins, this is a new evidence for LSD1 as a functional regulator of miRNA. On the other hand, our data suggested that promoting the secretion of miR-142-5p using small extracellular vesicles as vehicles is a new mechanism for LSD1 abrogation to down-regulate intracellular miR-142-5p. Taken together, this study uncovered a new mechanism for LSD1 that can contribute to gastric cancer migration by facilitating miR-142-5p to target CD9., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Liver fibrosis leads to over one million deaths annually worldwide. Hepatic stellate cells (HSCs) have been identified as the main executors of liver fibrosis. Unfortunately, no drug has yet been approved for clinical use against liver fibrosis, largely because the tested drugs have been unable to access HSCs and efficiently remove the collagen accumulation involved in fibrogenesis. Here, we designed an efficient HSC-targeting lipid delivery system that carried dual siRNAs intended to both inhibit collagen synthesis and promote collagen degradation, with the goal of realizing enhanced anti-liver fibrosis by bidirectional regulation of collagen accumulation. The delivery system was constructed by using amphiphilic cationic hyperbranched lipoids (C 15 -PA) for siRNA complexation and helper lipoids (cholesterol-polyethylene glycol-vitamin A, Chol-PEG-VA) for HSCs targeting. The generated vitamin A-decorated and hyperbranched lipoid-based lipid nanoparticles (VLNPs) showed excellent gene-binding ability and transfection efficiency, and enhanced the delivery of siRNAs to HSCs. Fibrotic mice treated with dual siRNA-loaded VLNPs showed a great reduction in the collagen accumulation seen in this model; the enhanced effect of bidirectional regulation reduced the collagen accumulation level in treated mice to almost that seen in normal mice. There was no notable sign of toxicity or tissue inflammation in mice exposed to repeated intravenous administration of the dual siRNA-loaded VLNPs. In conclusion, our results indicate that biocompatible VLNPs designed to exploit precise targeting and an effective bidirectional regulation strategy hold promise for treating liver fibrosis., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

As hepatic stellate cells (HSCs) are essential for hepatic fibrogenesis, HSCs targeted nano-drug delivery system is a research hotspot in liver fibrosis therapy. However, the excessive deposition of fibrosis collagen (mainly collagen I) in the space of Disse associated with hepatic fibrogenesis would significantly hinder nano-formulation delivery to HSCs. Here, we have prepared a collagenase I and retinol co-decorated polymeric micelle that possess nanodrill-like and HSCs-target function based on poly-(lactic-co-glycolic)-b-poly (ethylene glycol)-maleimide (PLGA-PEG-Mal) (named CRM) for liver fibrosis therapy. Upon encountering collagen I barrier, CRM exerted a nanodrill-like function, efficiently degrading pericellular collagen I and showing greater uptake by human HSCs than other micelle formulations. Besides, CRM could realize excellent accumulation in the fibrotic liver and accurate targeting to activated HSCs in mouse hepatic fibrosis model. Moreover, CRM loaded with nilotinib (CRM/NIL), a second-generation tyrosine kinase inhibitor used in the treatment of liver fibrosis, showed optimal antifibrotic activity. This work suggests that CRM with dual function is an efficient carrier for liver fibrosis drug delivery and collagenase I decorating could be a new strategy for building more efficient HSCs targeted nano-drug delivery system., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Although studies have shown the concomitant occurrence of autophagic and programmed cell death (PCD) in plants, the relationship between autophagy and PCD and the factors determining this relationship remain unclear. In this study, seedlings of the wheat cultivar Jimai 22 were used to examine the occurrence of autophagy and PCD during polyethylene glycol (PEG)-8000-induced drought stress. Autophagy and PCD occurred sequentially, with autophagy at a relatively early stage and PCD at a much later stage. These findings suggest that the duration of drought stress determines the occurrence of PCD following autophagy. Furthermore, the addition of 3-methyladenine (3-MA, an autophagy inhibitor) and the knockdown of autophagy-related gene 6 (ATG6) accelerated PEG-8000-induced PCD, respectively, suggesting that inhibition of autophagy also results in PCD under drought stress. Overall, these findings confirm that wheat seedlings undergo autophagic survival under mild drought stress, with subsequent PCD only under severe drought., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article.

Amino acids play key roles in cellular protein biosynthesis and energy metabolism pathways. In this study, a simple, rapid and sensitive method was developed for the simultaneous determination of 24 free amino acids in cell samples using hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry (HILIC-MS/MS). Cell samples were deproteinized with methanol/H 2 O (80:20, v/v) without intricate derivatization process. The analytes were separated on a Waters BEH Amide column (2.1 mm × 100 mm, 1.7 μm), and accomplished within 5 min at a flow rate of 0.2 mL/min. The good linearity was obtained for all analytes (r 2  > 0.99) with the limits of quantification from 0.1 to 25 ng/mL. The intra- and inter-day precision ranged from 0.35 to 10.36% and from 2.22 to 9.93%, respectively. The recoveries of most analytes were between 80% and 120% with RSD less than 10.0%. The developed method was then applied to the direct analysis of 24 underivatized amino acids in human gastric cancer cell line MGC803 treated with the antitumor candidate drug J3, and significant differences in the concentration levels of amino acids were also assessed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To explore the relationship between AK5 and gastric cancer., Materials and Methods: The in situ levels of AK5 in the GC tissues from 255 patients were detected by immunohistochemistry (IHC). The correlation between AK5 expression and the clinicopathological parameters was analyzed by Pearson correlation, and the prognostic factors were identified by Cox regression analysis. The transcriptome data of 14 human GC cell lines deposited in the CCLE database were analyzed, and two lines were selected for functional studies. AK5 was knocked down in the AZ521 and MKN74 cells using siRNA, and their proliferation and apoptosis were evaluated by Cell Counting Kit-8 (CCK-8) assay and Annexin-V staining, respectively. In addition, the apoptosis and autophagy of the markers were detected by Western blotting., Results: Patients expressing high AK5 levels in the tumor tissues had significantly shorter survival compared to low-expressing group. In addition, AK5 expression was associated with T stage and N stage and was an independent prognostic factor. AK5 knockdown in the AZ521 and MKN74 cells significantly inhibited proliferation and autophagy, and increased apoptosis., Conclusions: AK5 is a potential prognostic marker and therapeutic target for GC.

Background: Wnt1-inducible signaling pathway protein 1 (WISP1) is upregulated in several types of human cancer, and has been implicated in cancer progression. However, its clinical implications in gastric cancer (GC) remain unclear., Aim: To explore the expression pattern and clinical significance of WISP1 in GC., Methods: Public data portals, including Oncomine, The Cancer Genome Atlas database, Coexpedia, and Kaplan-Meier plotter, were analyzed for the expression and clinical significance of WISP1 mRNA levels in GC. One hundred and fifty patients who underwent surgery for GC between February 2010 and October 2012 at the Affiliated Hospital of Jiangnan University were selected for validation study. WISP1 levels were measured at both the mRNA and protein levels by RT-qPCR, Western blot analysis, and immunohistochemistry (IHC). In addition, the in situ expression of WISP1 in the GC tissues was determined by IHC, and the patients were accordingly classified into high- and low-expression groups. The correlation of WISP1 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses. WISP1 was knocked down by RNA interference. The 50% inhibitory concentration of oxaliplatin was detected by CellTiter-Blue assay., Results: WISP1 levels at both the mRNA and protein levels were remarkably upregulated in GC tissues compared to normal tissues. Moreover, IHC revealed that WISP1 expression was associated with T stage and chemotherapy outcome, but not with lymph node metastasis, age, gender, histological grade, or histological type. GC patients with high WISP1 expression showed a poor overall survival. Multivariate survival analysis indicated that WISP1 was an important prognostic factor for GC patients. Mechanistically, knock-down of WISP1 expression enhanced sensitivity to oxaliplatin by reducing DNA repair and enhancing DNA damage., Conclusion: Significantly upregulated WISP1 expression is associated with cancer progression, chemotherapy outcome, and prognosis in GC. Mechanistically, knock-down of WISP1 expression enhances oxaliplatin sensitivity by reducing DNA repair and enhancing DNA damage. WISP1 may be a potential therapeutic target for GC treatment or a potential biomarker for diagnosis and prognosis., Competing Interests: Conflict-of-interest statement: The authors report no conflicts of interest in this work., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Hepatitis B e antigen (HBeAg) seroconversion represents an endpoint of treatment of chronic hepatitis B virus (HBV) infections., Methods: We have studied whether levels of serum hepatitis B virus ribonucleic acid (HBV RNA) during pegylated interferon alfa-2a treatment might be helpful for predicting HBeAg seroconversion. 61 HBeAg-positive chronic hepatitis B (CHB) patients treated with pegylated interferon alfa-2a alone or in combination with adefovir (10 mg/day) for 48 weeks were included in this retrospective analysis. Response was defined as HBeAg seroconversion at 24 weeks posttreatment. Receiver operating characteristic analyses were used to identify baseline and on-treatment HBV RNA levels associated with response., Results: Twenty-two of 61 (36.1%) patients achieved a response. Baseline HBV RNA levels were lower in responders than in nonresponders (4.55 ± 1.19 and 5.90 ± 1.13 copies/mL, respectively, P = 0.001). Baseline HBV RNA cut off level (200,000 copies/mL) provided a positive predictive value (PPV) of 56.0% and a negative predictive value (NPV) of 77.8%. HBV RNA level (3000 copies/mL) at week 12 provide a PPV of 75.0% and a NPV of 82.8%. Moreover, HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in patients with HBV RNA ≤ 200,000 copies/mL at baseline and HBV RNA ≤ 3000 copies/mL at week 12 (92.9%) versus others (12.5%) (All P < 0.05)., Conclusions: In Conclusions, serum HBV RNA levels may serve as a novel tool for prediction of HBeAg seroconversion during therapy with pegylated interferon alfa-2a in HBeAg-positive CHB patients.

Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals 1,2 . However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(II) and the integrity of its binding motif His-X-Asp, which is conserved in Fe-dependent dioxygenases 3 . However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate 4 , CMD1 uses L-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO 2 . The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.

Novel total syntheses of oxoaporphine alkaloids such as liriodenine, dicentrinone, cassameridine, lysicamine, oxoglaucine and O -methylmoschatoline were developed. The key step of these total syntheses is Cu-catalyzed conversion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to 1-benzoyl-isoquinolines (1-Bz-IQs) via tandem oxidation/aromatization. This novel Cu-catalyzed conversion has been studied in detail, and was successfully used for constructing the 1-Bz-IQ core., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Liver fibrosis refers to excessive accumulation of hepatic collagen, which is primarily produced by activated hepatic stellate cells (HSCs). No effective drugs are clinically available to treat this condition, reflecting the fact that antifibrotic drugs do not specifically target activated HSCs. Here, we report the synthesis and evaluation of poly (lactide-co-glycolide)-polyspermine-poly (ethylene glycol)-vitamin A (PLGA-PSPE-PEG-VA), and activated HSC-targeted, biocompatible amphiphilic polymers for co-delivery of chemical (silibinin) and genetic (siCol1α1) drugs that synergistically suppress collagen I accumulation in fibrogenesis. PLGA-PSPE-PEG-VA self-assembled into core-shell polymeric micelles (PVMs) at low concentrations. After loading with silibinin and siCol1α1, the resulting chemical/genetic drug-loaded PVMs (CGPVMs) exhibited a small particle size and a slightly positive surface. CGPVMs had very low cytotoxicity and hemolytic activity in vitro and were well tolerated in mice, with no liver toxicity or inflammation. Importantly, CGPVMs effectively accumulated in fibrotic livers and specifically targeted activated HSCs. As expected CGPVMs more efficiently decreased collagen I production and ameliorated liver fibrosis compared with chemical drug (silibinin)-loaded PVMs (CPVMs) or genetic drug (siCol1α1)-loaded PVMs (GPVMs) only. These results indicate that CGPVMs are a promising tool for targeted delivery of chemogenes to activated HSCs in the treatment of liver fibrosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A green chemical method for mild oxidation of 1,2,3,4-tetrahydroisoquinolines (THIQs) and 3,4-dihydroisoquinolines (DHIQs) has been developed using air (O 2 ) as a clean oxidant. DHIQs and THIQs could be efficiently oxidized to isoquinolines in dimethyl sulfoxide at 25 °C under an open air atmosphere with CuBr 2 (20 mol %) as the catalyst; different bases [NaOEt and/or 1,8-diazabicyclo[5,4,0]undec-7-ene] were used for the reaction according to the patterns of substituents (R 1 , R 2 )., Competing Interests: The authors declare no competing financial interest.

Wnt signaling pathway plays important roles in the development and homeostasis of multicellular organisms. Through their bindings with the Frizzled receptors, the Wnt ligands regulate a wide range of developmental processes, such as axis patterning, cell division, and cell fate specification. Wnt signaling plays vital roles in the development of inner ear of the mouse. In the early stages of inner ear development, Wnt signaling specifies the size of the placode and the formation of the otic vesicle. In later stages, Wnt signaling mediates hair cell specification and orients the stereociliary bundles in a uniform direction. In this review, we summarize the current knowledge on the roles of Wnt signaling in hair cell differentiation and regeneration, which may provide references and insights for investigators in the field.

Information on the endemic situation of malaria in the joint malaria control zone of Guizhou and Guangxi Provinces from 2012 to 2013 was collected. Blood test results from fever patients and the healthy population were obtained. The spatiotemperal and occupational distributions of malaria cases were analyzed. During 2012-2013, blood tests were performed in 253 606 local residents and 11 212 returning residents in the joint area, as well as in 19 843 migrants from outside the area, resulting in discovery of 30 Plasmodium-infected cases only in the returning residents. All the 30 cases were imported from abroad, most of whom were electricity workers returning from the Africa. Among them, 28 cases were reported in 6 counties in Guangxi, and 2 in 2 counties/cities in Guizhou.

p21 is a cyclin-dependent kinase inhibitor, which can arrest cell proliferation and serve as a tumor suppressor. Though many studies were published to assess the relationship between p21 rs1059234 polymorphism and various cancer risks, there was no definite conclusion on this association. To derive a more precise quantitative assessment of the relationship, a large scale meta-analysis of 5,963 cases and 8,405 controls from 16 eligible published case-control studies was performed. Our analysis suggested that rs1059234 was not associated with the integral cancer risk for both dominant model [(T/T+C/T) vs C/C, OR=1.00, 95% CI: 0.84-1.18] and recessive model [T/T vs (C/C+C/T), OR=1.03, 95% CI: 0.93-1.15)]. However, further stratified analysis showed rs1059234 was greatly associated with the risk of squamous cell carcinoma of head and neck (SCCHN). Thus, larger scale primary studies are still required to further evaluate the interaction of p21 rs1059234 polymorphism and cancer risk in specific cancer subtypes.

The α2 adrenoceptor is highly enriched in spinal dorsal horn and involved in descending noradrenergic pain modification. Following peripheral tissue injury, intrathecal application of α2 adrenoceptor agonists effectively alleviates the pathological pain hypersensitivity, although the precise mechanisms are not fully understood. The present study induced inflammatory pain by intraplantar injection of Complete Freund's Adjuvant (CFA), and prepared the spinal cord slices to assay the possible influence of α2 adrenoceptor agonist clonidine on the synaptic transmission mediated by NMDA receptor (NMDAR), a critical player in spinal sensitization. Whole-cell patch clamp recordings in lamina II neurons illustrated that clonidine significantly decreased the amplitudes of NMDAR-mediated monosynaptic responses in inflamed mice through activation of α2A-subtype adrenoceptor. No significant alteration in the paired-pulse ratio before and after clonidine application indicated the postsynaptic origin. Intracellular loading of nonhydrolyzable GDP analog GDP-β-S blocked, whereas direct inhibition of cAMP-dependent protein kinase (PKA) mimicked, the inhibitory effect of clonidine on NMDAR currents, implicating that Gαi protein/PKA signaling was involved in clonidine action. Biochemical analysis in vivo revealed that intrathecal clonidine administration specifically decreased the content of GluN2B subunit-containing NMDAR at synaptosomal membrane fraction, a result associated closely with the alleviation of inflammatory pain. Electrophysiological recordings in vitro further demonstrated that GluN2B receptor-selective inhibitor ifenprodil dramatically reduced NMDAR synaptic responses in inflamed mice and more importantly, occluded the synaptic inhibition produced by clonidine. These data suggested that the noradrenergic suppression of inflammatory pain might involve the blockade of GluN2B receptor-mediated nociceptive transmission in spinal dorsal horn., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The fast inhibitory synaptic transmission mediated by the γ-aminobutyric acid type A receptor (GABAA R) within spinal dorsal horn exerts a gating control over the synaptic conveyance of nociceptive information from the periphery to higher brain regions. Although a large body of evidence has demonstrated that the impairment of GABAergic inhibition alone is sufficient to elicit pain hypersensitivity in intact animals, the underlying mechanisms remain to be characterized. The present study shows that Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is an important signaling protein downstream of reduced GABAergic inhibition. We found that pharmacological removal of inhibition by intrathecal application of the GABAA R antagonist bicuculline significantly enhanced the autophosphorylation of CaMKII at Thr286 in spinal dorsal horn of mice. In addition to increased CaMKII activity, bicuculline also promoted CaMKII interaction with N-methyl-D-aspartate (NMDA)-subtype glutamate receptors and induced the translocation of CaMKII from cytosolic compartments to the synaptosomal membrane fraction. Immunoblotting analysis revealed that the phosphorylation levels of NMDA receptor NR2B subunit at Ser1303 and of AMPA-subtype glutamate receptor GluR1 subunit at Ser831, two important CaMKII phosphorylation sites, were substantially enhanced after bicuculline application. Behavioral tests illustrated that intrathecal administration of the CaMKII inhibitor KN-93, NMDA receptor antagonist D-APV, or AMPA receptor antagonist GYKI 52466 effectively ameliorated the mechanical allodynia evoked by bicuculline. These data thus indicate that CaMKII signaling is critical for the reduced inhibition to evoke spinal sensitization., (Copyright © 2013 Wiley Periodicals, Inc.)

Diterpenes, present in many medicinal plants, have been the focus of continuous studies for the development of new anticancer agents. ZBB-006 is a new synthetic diterpenoid derivative which exhibited significant anti-proliferation activity against various cancer cell lines in our previous study. Here, we investigated the antitumor effect of ZBB-006 and its potential mechanisms in the human hepatocellular carcinoma cell line HepG2, both in vitro and in vivo. We found that oral administration of ZBB-006 effectively suppressed the growth of HepG2 xenograft tumor in nude mice without body weight decline as compared with the control group. Meanwhile, the growth inhibitory effect of ZBB-006 on HepG2 cells was observed with MTT assay. Apoptosis induced by ZBB-006 in HepG2 cells was evidenced by DAPI staining and Annexin V/PI double staining assay. ZBB-006 also dissipated the mitochondrial membrane potential (ΔΨm) apparently as revealed by JC-1 staining. Furthermore, the cleavage of PARP, activation of caspase-3 and caspase-9 but not caspase-8 was demonstrated by western blot assay both in vitro and in vivo. Additionally, the proapoptotic protein Bax was markedly elevated, while the antiapoptotic protein Bcl-2 was downregulated. Collectively, our data indicated that ZBB-006 exerted a strong antitumor effect on HepG2 cells by initiating the mitochondrial-dependent apoptosis, and it has potential to be explored as a new promising therapeutic agent against human hepatoma.

Objective: To study the effect of lower-molecular weight heparin in the prevention of pancreatic encephalopathy (PE) in the patient with severe acute pancreatitis (SAP)., Methods: Two hundred sixty-five SAP patients were randomly divided into 2 groups: (1) conventional treatment group (C group, n = 130) and (2) conventional treatment plus lower-molecular weight heparin treatment group (LT group, n = 135). The clinical parameters, laboratory parameters and computed tomographic (CT) score of pancreatic necrosis (CTSPN), incidence of PE, and mortality in the 2 groups were compared., Results: On admission, all the clinical parameters, laboratory parameters, and CTSPN in the 2 groups were not significantly different (P > 0.05). However, 1 to 2 weeks after treatment, the symptoms and signs improvement rate, the levels of blood and urine amylase, the CT score, and the Acute Physiology and Chronic Health Evaluation II score in the LT group were obviously lower than those in the C group (P < 0.05-0.01), and PE occurrence rate, mortality, and mean hospital stay in LT group were obviously lower than those in the C group (P < 0.05-0.01)., Conclusions: Lower-molecular weight heparin can enhance the effect of conventional treatment of SAP and can markedly decrease the PE incidence and improve the survival rate of SAP. Lower-molecular weight heparin is a simple, safe, less expensive, and effective method for treatment of SAP. It can be used in every hospital.

Objective: To study the effect of low molecular weight heparin (LMWH) in the treatment of severe acute pancreatitis (SAP)., Methods: A total of 265 SAP patients were randomly divided into two groups: firstly, the conventional treatment group (C group, n = 130; and secondly the conventional treatment plus the LMWH treatment group (LT group, n = 135). The clinical parameters, laboratory parameters and computed tomography (CT) score of pancreatic necrosis (CTSPN) in the two groups were compared., Results: On admission, all the clinical parameters, laboratory parameters and CTSPN in the two groups were not significantly different (p > 0.05). However, after treatment, in LT group, the clinical presentation improvement rate and laboratory parameters improvement were significantly higher than those in C group (p < 0.05-0.01), and the acute physiology and chronic health evaluation (APACHE) II score, complication rate, mortality and mean hospital stay in LT group were obviously lower than those in C group (p < 0.05-0.01). The CT score in LT group was much lower than that in C group (p < 0.05). Two weeks after treatment FBI decreased obviously in C group, but not in LT group, and no haemorrhagic complications occurred., Conclusions: LMWH can enhance the effect of conventional treatment for SAP, and can markedly decrease the mortality of SAP. LMWH is a simple, safe, economic and effective method for treatment of SAP. It is can be used in every hospital.

We report a rare case of acute pulmonary and cerebral complication after transarterial chemoembolisation (TACE) for inoperable hepatocellular carcinoma. The case involved a large tumor and hepatic vein invasion. Nonspecific pulmonary and cerebral symptoms such as acute dyspnoea and transient consciousness loss developed in the patient, a 49-year-old woman, following the TACE due to pulmonary and cerebral oil embolism. The chest and brain conditions of this patient improved after some supportive therapies and nursing interventions. She also subsequently completed the other three procedures of TACE.

In a wild-type strain of Saccharomyces cerevisiae, a hotspot for meiotic recombination is located upstream of the HIS4 gene. An insertion of a 49-bp telomeric sequence into the coding region of HIS4 strongly stimulates meiotic recombination and the local formation of meiosis-specific double-strand DNA breaks (DSBs). When strains are constructed in which both hotspots are heterozygous, hotspot activity is substantially less when the hotspots are on the same chromosome than when they are on opposite chromosomes.

Meiotic double-strand DNA breaks (DSBs), the lesions that initiate meiotic recombination at the HIS4 recombination hot spot, occur in a region upstream of the coding sequence associated with multiple DNase I-hypersensitive sites. Mutations in transcription factors that lead to loss of the DSBs result in the loss of some but not all DNase I-hypersensitive sites in the upstream region. A meiosis-specific change in chromatin structure is detected in strains with the wild-type hot spot but not in strains with alterations that elevate or reduce hot spot activity. The position and intensity of micrococcal nuclease-hypersensitive sites correlate poorly with the sites of DSB formation.