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Background: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma.Objective: To compare the clinical benefit of montelukast, a once-daily oral leukotriene receptor antagonist; placebo; and inhaled beclomethasone.Design: Randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 12-week study.Setting: 36 sites worldwide.Patients: 895 patients 15 to 85 years of age with chronic asthma and an FEV1 50% to 85% of predicted.Interventions: Montelukast, 10 mg once daily at bedtime; inhaled beclomethasone, 200 microg twice daily, administered with a spacer device; or placebo.Measurements: Primary end points were daytime asthma symptom score and FEV1. Secondary end points were peak expiratory flow rates in the morning and evening, as-needed beta-agonist use, nocturnal awakenings, asthma-specific quality of life, and worsening asthma episodes.Results: Over the 12-week treatment period, the average percentage change from baseline in FEV1 was 13.1% with beclomethasone, 7.4% with montelukast, and 0.7% with placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). The average change from baseline in daytime symptom score was -0.62 for beclomethasone, -0.41 for montelukast, and -0.17 for placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). Each agent improved peak expiratory flow rates and quality of life, reduced nocturnal awakenings and asthma attacks, increased the number of asthma-control days, and decreased the number of days with asthma exacerbations (P < 0.001 for each active treatment compared with placebo for each end point; P < 0.01 for beclomethasone compared with montelukast for each end point). Although beclomethasone had a greater mean clinical benefit than montelukast, montelukast had a faster onset of action and a greater initial effect. The two agents caused similar decreases in peripheral blood eosinophil counts (P < 0.05 for each agent compared with placebo). Both agents had tolerability profiles similar to that of placebo over the 12-week study.Conclusions: Although beclomethasone had a larger mean effect than montelukast, both drugs provided clinical benefit to patients with chronic asthma. This finding is consistent with the use of these agents as controller medications for chronic asthma. [ABSTRACT FROM AUTHOR]

Introduction: The heterogeneity of hepatocellular carcinoma (HCC) is linked to tumor malignancy and poor prognosis. Nevertheless, the precise mechanisms underlying the development of the cholangiocellular phenotype (CCA) within HCC remain unclear. Emerging studies support that the cross-talk among the host cells within tumor microenvironment (TME) sustains the cancer cell plasticity., Objectives: This study sought to identify the specific cell types involved in the formation of CCA and to elucidate their functional roles in the progression of HCC., Methods: Single-cell RNA sequencing was employed to identify the specific cell types involved in the formation of CCA. Both in vitro and vivo analyses were used to identify the tumor-associated senescent ECs and investigate the function in TME. The diethylnitrosamine-induced model was utilized to investigate the interaction between senescent ECs and MSCs, aiming to elucidate their synergistic contributions to the progression of CCA., Results: Using single-cell RNA sequencing, we identified a distinct senescent-associated subset of endothelial cells (ECs), namely CD34 + CLDN5 + ECs, which mainly enriched in tumor tissue. Further, the senescent ECs were observed to secrete IGF2, which recruited mesenchymal stem cells (MSCs) into the TME through IGF2R/MAPK signaling. In primary liver cancer model, MSCs exhibited a strong tumor-promoting effect, increasing the CCA and tumor malignancy after HCC formation. Interestingly, knockdown of IGF2R expression in MSCs inhibited the increase of CCA caused by MSCs in HCC. Meanwhile, it was revealed that MSCs released multiple inflammatory and trophic-related cytokines to enhance the cancer stem cell-like characteristics in HCC cells. Finally, we demonstrated that CEBPβ up-regulated IGF2 expression in tumor senescent ECs by combining with Igf2-promtor-sequence., Conclusions: Together, our findings illustrated that tumor associated senescent ECs in HCC recruited the MSCs into TME, enhancing cancer stem cell (CSC)-like features of HCC cells and contributing to the CCA formation., 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. Published by Elsevier B.V.)

Purpose: To explore the value of tissue quantitative diffusion analysis of ultrasound elastography in the diagnosis of early-stage chronic kidney disease (CKD)., Methods: The observation group comprised 54 patients with early-stage CKD treated at Fuzhou No 7 Hospital, and the control group consisted of 40 healthy individuals who underwent physical examinations at the same hospital. The renal parenchyma of the participants were examined using ultrasonography, color Doppler ultrasonography, and tissue quantitative diffusion analysis of ultrasound elastography. Renal dimensions (diameter, thickness, and renal parenchyma thickness), interlobar artery blood flow parameters, and 11 elastic characteristic values were analyzed and compared between the two groups. The area under the receiver-operating characteristic (ROC) curve, cut-off values, sensitivity, and specificity were calculated using the ROC curve analysis., Results: There were no significant differences in the blood flow parameters of the interlobar artery and the dimensions of renal meridians between the two groups. In the observation group, the mean (MEAN) decreased, while the blue area ratio and skewness, increased, compared to the control group (p < 0.05). In addition, the ROC curve revealed that the blue area ratio, MEAN, and skewness had significant diagnostic value (the area under the curve > 0.7). Notably, the best cut-off value of the MEAN was found to be 106, indicating that a MEAN value less than 106 represented early-stage CKD. Also, this cutoff value had a sensitivity of 80% and a specificity of 81%., Conclusion: Tissue quantitative diffusion analysis of ultrasound elastography can quantitatively evaluate renal parenchymal damage in early-stage CKD using quantitative diffusion parameters, with the MEAN parameter, having a cutoff of 106, being particularly effective. This parameter and cutoff value offer a valuable tool for the early detection and diagnosis of CKD, potentially improving patient outcomes through earlier intervention., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

This study aimed to investigate the effects of wild Cordyceps sinensis on chronic obstructive pulmonary disease (COPD) rats through metabolomics approach, combined with biochemical parameters evaluations. Consequently, C. sinensis exhibited regulatory effects on the lung's metabolic profiles in COPD rats. Treatment with C. sinensis potentially modulated glycerophospholipid metabolism, glutathione metabolism, and tryptophan metabolism, thereby alleviating oxidative stress (by decreasing MDA and GSSG, while increasing SOD and GSH) and inflammatory response (by inhibiting TNF-α, IL-8, and MMP-9) in COPD rats while improving lung tissue damage.

Magnetic impurities in superconductors are of increasing interest due to emergent Yu-Shiba-Rusinov (YSR) states and Majorana zero modes for fault-tolerant quantum computation. However, a direct relationship between the YSR multiple states and magnetic anisotropy splitting of quantum impurity spins remains poorly characterized. By using scanning tunneling microscopy, we systematically resolve individual transition-metal (Fe, Cr, and Ni) impurities induced YSR multiplets as well as their Zeeman effects in the K 3 C 60 superconductor. The YSR multiplets show identical d orbital-like wave functions that are symmetry-mismatched to the threefold K 3 C 60 (1 1 1) host surface, breaking point-group symmetries of the spatial distribution of YSR bound states in real space. Remarkably, we identify an unprecedented fermion-parity-preserving quantum phase transition between ground states with opposite signs of the uniaxial magnetic anisotropy that can be manipulated by an external magnetic field. These findings can be readily understood in terms of anisotropy splitting of quantum impurity spins, and thus elucidate the intricate interplay between the magnetic anisotropy and YSR multiplets., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

The Ambu Aura-i laryngeal mask is considered to be a device for blind intubation as well as for fiberoptic guided intubation. The novel video laryngeal airway mask SaCoVLM is a supraglottic airway device that allows intubation under direct vision. We hypothesized that success rates for device placement and tracheal intubation with the SaCoVLM would be comparable with the Ambu Aura-i mask. A prospective, randomized clinical trial was conducted from March 2021 to December 2021. One hundred and twenty patients were enrolled and randomized in the study. Direct intubation was performed with the SaCoVLM, and fiberoptic guided intubation was performed with the Ambu Aura-i mask. The primary outcome measure was the first success rate of LMA placement. Secondary outcome measures were the time from device placement and time from endotracheal intubation (as well as the time for LMA removal after successful intubation), differences in airway leak pressure, fiberoptic grade of the laryngeal view, and incidence of blood staining. The first success rate of LMA placement was similar for the two devices. There was no difference in the time for successful endotracheal intubation between the Ambu Aura-i and SaCoVLM groups (24.1 s ± 6.3 versus 25.7 s ± 2.1; p > 0.05). The time for removal was slower in the SaCoVLM group than in the Ambu Aura-i group (20.8 s ± 0.8 versus 14.7 s ± 6.1; p < 0.01). The airway leak pressure was higher in the SaCoVLM group than in the Ambu Aura-i group (27.0 s ± 1.0 versus 22.3 s ± 3.6; p < 0.01), and the incidence of blood staining was higher in the SaCoVLM group (16.7%). The SaCoVLM has an overall comparable performance to the Ambu Aura-i mask. However, the SaCoVLM is better relative to direct intubation without the assistance of a flexible intubation scope, which reduces the device's demand., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism., Methods: To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS., Results: We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway., Conclusion: In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway., 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 © 2023 Liang, Zhang, Liu, Zong, Gao, Li, Zhao, Zhao, Wei, Zhang and Han.)

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8 + T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1 -deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

Backgrounds: To preliminary evaluate the application of novel SaCoVLM video laryngeal mask -guided intubation for anesthetized children., Methods: One hundred twenty-four children with microtia (ages 5-15 years,) who required general intubation anaesthesia, were enrolled in the study. After induction of general anesthesia,guided tracheal intubation under direct vision of the SaCoVLM was performed. Our primary outcome was first-pass success rate of guided tracheal tube placement. Secondary outcome included glottic visualization grades, the first-attempt success rate of LMA placement, the time for LMA placement and time to endotracheal intubation as well as the time for LMA removal after successful intubation, the fiberoptic grade of laryngeal view, the baseline and postinduction hemodynamic parameters were also recorded,and the incidence 24 h complications after operation., Results: The first-pass success rate of guided tracheal tube placement was 91.1% (95%CI = 1.04-1.14), the status of glottic visualization was classified: grade 1 in 27cases, grade 2 in 36 cases, grade 3 in 41 cases and grade 4 in 20 cases. The first success rate of LMA placement was 92.7% (95%CI = 1.03-1.13), the time for LMA insertion was 15.7 (±9.1) s, intubation time was 30.9 (±17.6) s and withdrawl time was 24.9 (±9.3) s. The incidence of postoperative sore throat at 2 h was 29%, and 16.1% at 24 h, without dysphagia and hypoxia., Conclusion: The SaCoVLM video laryngeal mask-guided intubation is feasible in children, with a high success rate, could be a new promising device to guide intubation in airway management., Trial Registration: This study was approved by the University's Institutional Review Board and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (ChiCTR2200061481, http://www.chictr.org.cn . Principal investigator: Juan Zhi; Date of registration: 26/06/2022., (© 2023. The Author(s).)

Background: Advanced platelet-rich fibrin extract (APRFE) contains a high concentration of various cytokines that are helpful for improving stem cells repair function., Objective: However, the underlying mechanism of APRFE improving stem cell repairing is not clear., Methods: We produced APRFE by centrifuging fresh peripheral blood samples and isolated and identified human adipose-derived mesenchymal stem cells (ADMSCs). The abundance of cytokines contained in APRFE was detected by the Enzyme-linked immunosorbent assay (ELISA). The ADMSCs treated with or without APRFE were collected for transcriptome sequencing., Results: Based on the sequencing data, the expression profiles were contracted. The differentially expressed genes and lncRNA (DEGs and DElncRNAs) were obtained using for the differential expression analysis. The lncRNA-miRNA-mRNA network was constructed based on the miRNet database. The further enrichment analysis results showed that the biological functions were mainly related to proliferation, differentiation, and cell-cell function. To explore the role of APRFE, the protein-protein interaction network was constructed among the cytokines included in APRFE and DEGs. Furthermore, we constructed the global regulatory network based on the RNAInter and TRRUST database. The pathways in the global regulatory network were considered as the core pathways. We found that the DEGs in the core pathways were associated with stemness scores., Conclusion: In summary, we predicted that APRFE activated three pathways (tryptophan metabolism, mTOR signaling pathway, and adipocytokine signaling) to promote the proliferation and differentiation of ADMSCs. The finding may be helpful for guiding the application of ADMSCs in the clinic., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background & Aims: Capsaicin, a functional component of chili pepper, possesses anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to determine the property of capsaicin against hepatocarcinogenesis in vivo and investigate the role of the SIRT1/SOX2 pathway in the mode of action of capsaicin in hepatic progenitor cells (HPCs), which is related to hepatocarcinogenesis., Materials & Methods: We prepared a diethylnitrosamine-induced liver cancer model in rats to examine hepatocarcinogenesis, and delivered liposomal capsaicin through the subcutaneous transposition of the spleen to the liver. Liver sections from rats and hepatocarcinoma patients were stained for the markers of HPCs or SIRT1/SOX2 signaling. SIRT1/SOX2 signalling expression was measured using immunoprecipitation and western blot., Results: We found that capsaicin significantly inhibited hepatocarcinogenesis. Notably, capsaicin inhibited HPCs activation in vivo but did not induce apoptosis in the normal hepatic progenitor cell line in rats in vitro. This suggests that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs. Moreover, capsaicin can induce this inhibition by reducing the stability of SOX2. SIRT1 is overexpressed in liver cancer and acts as a tumor promoter via SOX2 deacetylation. Using immunoprecipitation, we identified direct binding between SIRT1 and SOX2. The capsaicin treatment resulted in SIRT1 downregulation which reduced deacetylation, and increased nuclear export as well as subsequent ubiquitous degradation of SOX2., Conclusions: Altogether, we report that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs via SIRT1/SOX2 signaling. It may serve as a promising therapeutic candidate for liver cancer., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Public health measures promoting compliance of COVID-19 vaccination requires understanding of knowledge, attitudes, and practices (KAP). This study explored the KAP and risk factors influencing COVID-19 vaccination, including changes in preventive practices before and after vaccination in a high-income country, Singapore. An online cross-sectional study among Singaporeans and permanent residents aged 21 years and older was conducted from July to August 2021. Univariate and multivariable logistic regressions using RStudio version 1.4.1106 was performed to assess associations between demographic factors, KAP, and vaccination status. P values < 0.05 were considered statistically significant. A total of 869 respondents completed the survey. Individuals with higher knowledge (adjusted odds ratio [aOR] = 2.00, P = 0.024), perceived efficacy (aOR = 1.19, P = 0.004), perceived safety (aOR = 1.20, P = 0.005), and willingness to uptake (aOR = 1.55, P < 0.001) scores were more likely to be vaccinated. There was a significant increase in the use of proper handwashing techniques among the vaccinated group before and after vaccinations. The governmental risk communication approaches have been useful in instilling high levels of vaccine knowledge. High levels of good attitudes about and knowledge of COVID-19 vaccination were associated with a high level of vaccination practices. Good perceived vaccine efficacy and confidence in government were also associated with positive vaccine uptake. This study paves the way for more targeted government measures to be implemented to improve vaccination rates of COVID-19 booster vaccines in a high-income country like Singapore.

Polymer flooding, as the most successful and well-known chemical EOR method was broadly applied around the world. Mostly, contrasted with Waterflooding, the production rate decrease during polymer flooding is smaller based on field application. Nevertheless, the production liquid rate decreased critically in the middle phase to late phase due to plugging, which could lead the way to poor flooding performance and fewer cumulative oil. In this work, first, we approached the affecting polymer plugging mechanism model on liquid production decrease to investigate the parameters such as; solid-phase concentration (SOLIDMIN), reacting frequency factor (FREQFAC) and others affecting components are all investigated consecutively. Secondly the model approached by cross-linked gel for the improvement of production liquid rate. The physical work was designed by a physical model, and then the polymer adsorption that generating blockage emerging in permeability diminish assessed by a mathematical model. The outcomes specify that the existence of this debris, excessive assemblage of solid-phase and the excessive reactant frequency factor has major mechanical and physical parameters effects on the reservoir throughout polymer flooding. Polymer flood model base case liquid ratio loss is 11.15 m 3 /day between the years 2014-08-01 to 2020-03-04. Comparing with the polymer flood model case 1, liquid ratio loss ranging to 1.97 m 3 /day between the years 2014-08-02 to 2020-03-03. While the oil ratio loss of the polymer flood base case model between the years 2015-07-08 to 2020-03-04 attained 12.4 m 3 /day contrasting with the polymer flood model case 1 oil ratio increase to 0.37 m 3 /day between the years 2014-08-04 to 2019-04-02. The cross-linked gel model base case liquid ratio loss is 2.09 m 3 /day between the years 2015-01-02 to 2020-02-03, while the oil ratio lost reached 9.15 m 3 /day between the years 2015-09-01 to 2020-02-03. Contrasting with the cross-linked gel model case 2 liquid ratio recovered from the loss and attained 25.43 m 3 /day in the year 2020-12-01, while the oil ratio is reached 15.22 m 3 /day in the year 2020-12-01. Polymer flood model examined through cross-linked gel model performed reliable outcomes by taking out the plugging, which also occasioned the reservoir production rate to decrease. With the application of cross-linked gel the affected parameters and the production rate have achieved an improvement., (© 2021. The Author(s).)

Objective: To investigate the therapeutic effects of Biejia Yugan Granule on hepatic fibrosis caused by compound factors in rats and its effect on TGF-β1/Smads signaling pathway. Methods: SD rats were randomly divided into blank control group, model control group, colchicine group, Biejia Yugan Granule low, medium and high dose (1.85, 3.70, 7.40 g/kg) groups ( n = 8 in each group). The rat model of hepatic fibrosis was established by treating with 5% alcohol 15 ml/kg (ig) everyday and injecting with 40% carbon tetrachloride (sc) twice a week for 42 days. The effects of Biejia Yugan Granule on liver function, liver index and water content, serum hepatic fibrosis related indicators, key proteins and gene expression of TGF-β1/Smads signaling pathway in rats were observed. Results: Biejia Yugan Granule at the doses of 1.85, 3.70 and 7.40 g/kg could decrease the serum levels of ALT, AST, ALP and HA, PCⅢ, C-Ⅳ, LN significantly, reduce the water content of liver tissue leads to the decrease of liver index, regulate the liver tissue TGF-β1, Smad3 mRNA and Smad7 mRNA expressions. Conclusion: Biejia Yugan Granule has obvious effects of reducing enzyme and protecting liver and inhibiting hepatic fibrosis, and inhibiting TGF-β1/Smads signaling pathway is one of its mechanisms of anti-hepatic fibrosis.

Objective: To investigate the effects of Butylphthalide (NBP) on airway mucus hypersecretion, interleukin-13 (IL-13) and tumor necrosis factor-α (TNF-α) in asthmatic mice. Methods: The mice were randomly divided into control group, asthma group, DEX group and high, medium and low doses of NBP (100, 50, 25 mg/kg) groups ( n =12). Ovalbumin (OVA) injection was sensitized on the 1st, 8th, and 15th day of the experiment, and OVA was inhaled on the 22nd day to stimulate for 5 weeks to replicate the asthma model, and 20 mg/kg of NBP was given for intervention before the challenge. Finally, the asthma behavior, the secretion of goblet cells and Mucin 5ac (Muc5ac)were observed, and meanwhile the viscosity of bronchoalveolar lavage fluid (BALF) and the levels of Muc5ac, IL-13 and TNF-α in BALF were measured by ELISA. Results: Compared with the control group, the degree of sneezing, nose scratching and asthma, the proliferation of airway epithelial goblet cells and secretion of Muc5ac in the asthma group were increased significantly ( P ＜0.01), meanwhile, the viscosity of BALF and the contents of Muc5ac, IL-13 and TNF-α were also increased significantly ( P ＜0.01). Compared with the asthma group, the above behavioral scores of asthma were decreased significantly ( P ＜0.01) after the intervention of 25, 50 and 100 mg/kg NBP, as well as the proliferation of airway epithelial goblet cells, secretion of Muc5ac, the viscosity of BALF and the contents of Muc5ac, IL-13 and TNF-α were significantly lower than those of the asthma group ( P ＜0.05, 0.01). Conclusion: NBP has the effect of anti-asthma by inhibiting mucus hypersecretion, and one of its mechanisms is to alleviate the abnormal expressions of IL-13 and TNF-α.

Three new diterpene alkaloids, tangutidines A-C (1-3), and four known alkaloids (4-7) were isolated from the whole plant of Aconitum tanguticum, from which amphoteric diterpene alkaloids (1-3) were obtained for the first time. The structures of 1-3 were elucidated by detailed interpretation of spectroscopic data, including MS and NMR data. All of them were evaluated for their cytotoxic activities., (© 2021. The Author(s).)

Sixteen diterpenoid alkaloids (DAs), including six aconitine-type alkaloids (5 and 9 - 13), seven 7,17-seco-aconitine-type alkaloids (1 - 4, 6 - 8), two napelline-type alkaloids (14 and 15) as well as one veatchine-type alkaloid (16), were isolated from the aerial parts of Aconitum flavum Hand.-Mazz. In which, flavumolines A - D (1 - 4) were four new ones, and flavumoline E (5) was reported as natural compound for the first time. Their chemical structures were elucidated by the analysis of extensive spectroscopic data. The inhibitory activities of these isolates on Ca v 3.1 low voltage-gated Ca 2+ channel, NO production in LPS-activated RAW264.7cells, five human tumor cell lines, as well as acetylcholinesterase (AChE) were tested., (© 2021. The Author(s).)

Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei ) is a famous Tibetan medicine for treating cardiovascular and gastrointestinal diseases.  We have shown that 70W protected against CCl 4 hepatotoxicity.  CCl 4 is metabolized via cytochrome P450 (CYP) to produce reactive metabolites. Whether 70W has any effect on CYPs is unknown and such effects should be compared with mercury compounds for safety evaluation.   Methods: Mice were given clinical doses of 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), and compared to HgCl 2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for seven days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic mRNA expression of Cyp1a2, Cyp2b10, Cyp3a11, Cyp4a10 and Cyp7a1, and corresponding nuclear receptors [aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα); farnesoid X receptor (FXR)]. In comparison, HgCl 2 and MeHg increased mRNA expression of Cyp1a2, Cyp2b10, Cyp4a10 and Cyp7a1 except for Cyp3a11, and corresponding nuclear receptors except for PXR. Western-blot confirmed mRNA results, showing increases in CYP1A2, CYP2B1, CYP2E1, CYP4A and CYP7A1 by HgCl 2 and MeHg only, and all treatments had no effects on CYP3A. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs and corresponding nuclear receptors, while HgCl 2 and MeHg produced significant effects.  Thus, the use of total Hg content to evaluate the safety of HgS-containing 70W is inappropriate., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Nie Y et al.)

Objective: Mycoplasma genitalium (Mg) is an opportunity pathogenic microorganism mainly transmitted through sexual contact. In recent years, scholars have paid more attention to Mg infection and pathogenicity. This study was aimed to understand the condition of Mg in the genitourinary tract of different populations in China and provide evidence for further study of its pathogenic characteristics. Methods: Cross-section studies of Mg infection in the Chinese community were searched by China National Knowledge Infrastructure (CNKI), Wanfang digital database, SinoMed, Pubmed, and Web of Science from database construction to March 10 th , 2020. Studies were sifted and screened independently by two evaluators based on inclusion and exclusion criteria, and Meta-analysis was conducted with R 1.1.463. If I 2 ≤50%, the fixed-effect model should be adopted, if I 2 >50%, the random effect model should be adopted, and through subgroup analysis, the source of heterogeneity should be found out as far as possible. Results: A total of 47 research articles were included in this article, all of which were medium and high-quality articles. There was no obvious publication bias, and the results were more reliable. The research contained 19 provinces and Hong Kong Special administrative region, including 519 healthy people, 10 504 patients from clinics or hospitals of sexual transmitted disease (STD), 3 200 on Gynecology and 1 624 on Urology, 1 082 patients with men who have sex with men(MSM), 1 842 patients with Female sex worker(FSW), and 3 691 patients with HIV/AIDS. The infection rate of Mg in the genitourinary tract of the healthy population was 0.94% (95% CI : 0.07%-2.78%), the infection rate of Mg was 11.58% (95% CI : 8.57%-14.97%), 15.22% (95% CI : 7.99%-24.27%), 7.32% (95% CI : 4.24%-11.16%) among patients from clinics or hospitals of STD, gynecology and urology respectively. The infection rate of MSM was 9.70% (95% CI : 3.06%-19.52%),the infection rate of FSW was 13.49% (95% CI : 11.97%-15.08%). The infection rate of Mg among HIV infected patients was 20.46% (95% CI : 13.67%-28.22%). Conclusions: The infection rate of Mg in a healthy population was low. Mg infection rate in the genitourinary tract of other groups was still higher, which is worthy of further attention.

Objective Asymptomatic carotid stenosis (ACS) is closely associated to the incidence of severe cerebrovascular diseases. Early identifying the individuals with ACS and its associated risk factors could be beneficial for primary prevention of stroke. This study aimed to investigate a machine-learning algorithm for the detection of ACS among high-risk population of stroke based on the associated risk factors.Methods A novel model of machine learning was utilized to screen the associated predictors of ACS based on 30 potential risk factors. The algorithm of this model adopted a random forest pattern based on the training data and then was verified using the testing data. All of the original data were retrieved from the China National Stroke Screening and Prevention Project (CNSSPP), including demographic, clinical and laboratory characteristics. The individuals with high risk of stroke were enrolled and randomly divided into a training group and a testing group at a ratio of 4:1. The identification of carotid stenosis by carotid artery duplex scans was set as the golden standard. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) was used to evaluate the efficacy of the model in detecting ACS.Results Of 2841 high risk individual of stroke enrolled, 326 (11.6%) were diagnosed as ACS by ultrasonography. The top five risk factors contributing to ACS in this model were identified as family history of dyslipidemia, high level of low-density lipoprotein cholesterol (LDL-c), low level of high-density lipoprotein cholesterol (HDL-c), aging, and low body mass index (BMI). Their weights were 11.8%, 7.6%, 7.1%, 6.1%, and 6.1%, respectively. The total weight of the top 15 risk factors was 85.5%. The AUC values of the model for detecting ACS with training dataset and testing dataset were 0.927 and 0.888, respectively.Conclusions This study demonstrated that the machine-learning algorithm could be used to identify the risk factors for ACS among high risk population of stroke. Family history of dyslipidemia may be the most important risk factor for ACS. This model could be a suitable tool to optimize the clinical approach for the primary prevention of stroke.

Objective: To analyze the incidence of heterotopic ossification after artificial cervical disc replacement with Discover disc, and to explore the effect of heterotopic ossification on postoperative radiological and clinical efficacy. Methods: From January 2010 to January 2015, 45 patients with cervical spondylosis underwent single-level artificial cervical disc replacement in Shanghai Changzheng Hospital, including 29 cases of cervical spondylotic myelopathy, 11 cases of cervical spondylotic radiculopathy and 5 cases of mixed cervical spondylosis. At the last follow-up, Mehren grading method was used for classification of heterotopic ossification, among which, grade 0-Ⅱ was defined as low grade ossification group, and 26 patients (16 male, 10 female) were enrolled in this group; grade Ⅲ-Ⅳ was defined as high grade ossification group, and 19 patients (12 males, 7 females) were included in this group. C(2-7) Cobb angle, cervical total range of motion and range of motion at index level were used to evaluate the radiological outcomes of the two groups. Japanese Orthopaedic Association (JOA) score, neck disability index (NDI) score and visual analogue scale (VAS) were used to evaluate the clinical outcomes of the two groups. The adjacent segment intervertebral disc height and range of motion were used to evaluate the effects of heterotopic ossification on adjacent segment. Results: All patients were followed up regularly for (98±18) months. There were no statistical differences between the two groups regarding to demographic data (all P> 0.05). There was no significant differences in C(2-7) Cobb angle and total range of motion between the two groups at the last follow-up (all P> 0.05), but range of motion at index level in the group with low grades was significantly higher than that in the group with high grades (7.8°±6.2° vs 2.6°±1.2°, t= 3.60, P< 0.05). There was no significant differences in JOA score, recovery rate and NDI score between the two groups (all P> 0.05). There was no significant differences in the adjacent segment intervertebral disc height before operation and at the last follow-up (both P> 0.05). There was no significant differences in range of motion at adjacent segment before operation ( P> 0.05), while range of motion at adjacent segment in the group with low grades was significantly lower than that in the group with high grades (9.5°±1.1° vs 10.6°±1.8° and 9.4°±1.4° vs 10.5°±1.7°, repectively, t= 2.54, 2.31, both P< 0.05). Conclusions: Heterotopic ossification does not affect the clinical outcomes, cervical curvature and cervical total range of motion after artificial cervical disc replacement with Discover disc. However, the higher grade of heterotopic ossification, the lower range of motion at index level and the higher range of motion at adjacent segment.

Objective: To investigate the prevention and treatment effect of Biejia Yugan Granule (BYG) on ethanol-induced hepatic fibrosis (EHF) rats. Methods: SD rats were randomly divided into blank control group, model group, BYG group, colchicine group and BYG low and BYG high dose groups ( n =8). The EHF rat model was established by intragastric edible ethanol with a gradually increased dose. Briefly, the rats of model group, colchicine group and BYG low and high dose groups were given gavage of 5 g/(kg·d) ethanol at week 1～4, 7 g/(kg·d) ethanol at week 5～8, 9 g/(kg·d) ethanol at week 9～12 and 9.5 g/(kg·d) ethanol at week 13～24. And the other two groups were treated with equal volume water. At the same time, the corresponding drugs were administrated daily: BYG group was treated with Biejia Yugan Granules 5.55 g/kg, colchicine group was treated with colchicine 0.1 mg/kg, BYG low-dose and high-group were treated with Biejia Yugan Granules 1.85 and 5.55 g/kg respectively. The blank control group and model control group were given the same amount of purified water. On the 169th day of the experiment, the effects of BYG on the macroscopic changes of rat liver organs, the water content of liver tissue and the pathological changes of fibrosis, the content of hydroxy proline (Hyp) in liver tissue and the expression levels of α-SMA and CREB were observed. Results: BYG at the doses of 1.85 and 5.55 g/kg could significantly improve the macroscopic changes of liver and pathological changes of liver tissue fibrosis in rats with EHF, reduce the contents of water and Hyp in liver tissue, and down-regulate the expressions of α-SMA and CREB. Conclusion: BYG has obvious effect on inhibiting EHF and one of its mechanisms is down-regulate the content of CREB.

Objective: To investigate the preventive and therapeutic effects of Qiwei Yugan Granule (QYG) on hepatic fibrosis in rats based on MMP-13/TIMP-1 imbalance. Methods: The rats were randomly divided into control group, model group, colchicine group (1.0×10 -4 g/kg) and QYG treated groups (3.7, 7.4, 14.8 g/kg) ( n =8). The rat model of hepatic fibrosis was established by injected with carbon tetrachloride subcutaneously for 4 weeks and treated with ethanol by gavage for 6 weeks. The effects of QYG on liver function, histopathology of liver, related indexes of serum liver fibrosis, and MMP-13, TIMP-1 in hepatic tissue were observed. Results: QYG at the doses of 14.8、7.4、3.7 g/kg could significantly decrease the serum levels of ALT, AST, HA, PCⅢ and C-Ⅳ, relieve the pathological changes of hepatic fibrosis, increase the activity of MMP-13, decrease the activity of TIMP-1 and alleviate the imbalance of MMP-13/TIMP-1. Among them, QYG had a certain trend of dose-effect relationship with TIMP-1 and MMP-13/TIMP-1 ( P ＜0.05, 0.01). Conclusion: QYG has the effect of preventing and treating liver fibrosis and one of mechanisms is to promote MMP-13/TIMP-1 to restore balance.

Objective: To investigate the therapeutic effects of Radix Angelicae Sinensis (RADA) on airway mucus hypersecretion and the tumor necrosis factor-α/ nuclear factor- κB (TNF-α/NF-κB) signaling pathway in Yin-deficiency asthma mice. Methods: KM mice were randomly divided into control group, model group, ambroxol group and RADA low, medium and high dose (2, 4 and 8 g/kg) group( n =12). Ovalbumin and the thyroid gland were used to replicate the model of Yin-deficiency asthma. Asthma symptoms in mice , immune globulin E (IgE) , TNF-α , and the expressions of Mucin 5ac (Muc5ac) and NF- κB in lung tissue were observed under the intervention of RADA. Results: RADA at the doses of 2,4 and 8 g/kg could alleviate the asthma symptoms of Yin-deficiency asthma mice significantly, reduce the levels of IgE in serum and TNF-α in bronchoalveolar lavage fluid (BALF), and inhibite the overexpressions of Muc5ac and NF- κB in lung tissue. Conclusion: RADA has significant anti-asthmatic effect. One of its mechanisms is to inhibit TNF-α/NF- κB signaling pathway and to alleviate airway mucus hypersecretion.

Hepatocellular carcinoma (HCC) generally occurs in the presence of chronic liver injury, often as a sequela of liver fibrosis. Hepatic progenitor cells (HPCs) are known to be capable of forming both hepatocytes and cholangiocytes in chronic liver injury, which are also considered a source of myofibroblasts and tumor-initiating cells, under carcinogenic circumstances. However, the underlying mechanisms that activate HPCs to give rise to HCC are still unclear. In current study, the correlation between HPCs activation and liver fibrosis and carcinogenesis was investigated in rats and human specimens. We analyzed the role of HPCs in tumorigenesis, by transplanting exogenous HPCs in a diethylnitrosamine-induced rat HCC model. Our data indicated that HPC activation correlated with hepatic fibrosis and hepatocarcinogenesis. We further found that exogenous HPC infusion promoted liver fibrosis and hepatocarcinogenesis, while lipopolysaccharides (LPS) played an important role in this process. However, results of our study indicated that LPS did not induce HPCs to form tumor in nude mice directly. Rather, LPS induced myofibroblast-like morphology in HPCs, which enhanced the tumorigenic potential of HPCs. Further experiments showed that LPS/Toll-like receptor 4 (TLR4) signaling mediated the differentiation of HPCs into myofibroblasts and enhanced the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which led to the aberrant expression of Ras and p53 signaling pathways in HPCs, and finally, promoted the proliferation and malignant transformation of HPCs, by long non-coding RNA regulation. Besides, examination of HCC clinical samples demonstrated that IL-6 and TNF-α production correlated with HPC activation, hepatic fibrosis, and HCC recurrence. Our study indicates that both myofibroblasts and tumor cells are derived from HPCs. HPC-derived myofibroblasts create tumor microenvironment and contribute to the proliferation and malignant transformation of HPCs. Furthermore, LPS present in the chronic liver inflammation microenvironment might play an important role in hepatocarcinogenesis, by regulating the plastic potential of HPCs.

Objective: To analyze the effect of serum free light chain (sFLC) on renal function and prognosis in patients with newly diagnosed multiple myeloma (MM)., Methods: The clinical data of 70 newly diagnosed MM patients who received sFLC examination in Fujian Medical University Union Hospital were retrospectively analyzed from April 2012 to November 2016. Univariate analysis was used to analyze the risk factors that associated with renal impairment (RI) and prognosis. Logistic regression and Kaplan-Meier analyze were used to analyze the roles of sFLC in RI and the prognosis., Results: Out of the 70 patients, 20 patients had RI at the initial diagnosis. Compared to normal renal function group, RI group had lower level of hemoglobin, elevated levels of serum uric acid, corrected calcium, serum creatinine, serum β2 microglobulin, and involved sFLC, higher proportion of patients with ISS stage III, involved sFLC≥500 mg/L, hemodialysis (all P＜0.05). Multivariate logistic regression analysis showed that serum uric acid≥430 μmol/L, ISS stage III and a involved sFLC≥500 mg/L were all the independent risk factors for RI in patients with newly diagnosed MM patients (all P＜0.05). Receiver operating characteristic (ROC) curves analysis showed that the involved sFLC was 705.0 mg/L, which was a best cut-off value area under curve (AUC) for prediting RI in patients with MM was 0.727 (P=0.003), sensitivity was 65.0% and specificity was 82.0%). After a median follow-up period of 31 (1-84) months, the median overall survival (OS) of patients with involved sFLC≥500mg/L and involved sFLC＜500 mg/L were 52.0 and 27.0 months, respectively, there was no statistically significant difference (P=0.137). There was also no statistically significant difference in median OS between the high sFLC ratio group (κ/λ＞32 or ＜0.03) and the low sFLC ratio group (0.03≤κ/λ≤32) (27 months vs 40 months, P=0.436)., Conclusion: The involved sFLC in the RI group is significantly higher than that in the normal renal function group in newly diagnosed MM patients. Serum uric acid≥430 μmol/L, ISS stage III and involved sFLC≥500 mg/L are the independent risk factors for RI. Monitoring sFLC in newly diagnosed MM patients is helpful to the prediction of RI, and the involved sFLC level or sFLC ratio may not affect the prognosis of newly diagnosed MM patients.

Background: Babao Dan (BBD), a traditional Chinese medicine, has been used as a complementary and alternative medicine to treat multifarious liver diseases. In this study, we aimed to observe its protective effect on ethanol-induced liver injury and explore potential mechanisms., Methods: Mice pretreated with BBD (0.125, 0.25 and 0.5 g/kg BW) were administrated by ethanol gavage (5 g/kg BW). Liver injury biomarkers and hepatic redox parameters were evaluated by histopathology as well as serum and hepatic content analysis. AML-12 cell was also utilized to determine the efficacy of BBD against ethanol-induced hepatotoxicity., Results: Drunkenness experiment showed that the latency was significantly increased and the drunken sleep time was decreased in mice pretreated with BBD. We then found that BBD could reduce hepatic lipid peroxidation and steatosis induced by ethanol exposure. BBD could also suppress ethanol-induced depletion of hepatic antioxidant enzyme. Besides that, BBD treatment lessened the induction of hepatic cytochrome P450 2E1, a major contributor to ethanol-mediated oxidative stress, and up-regulated the expression of nuclear factor erythroid 2-related factor 2 and its two transcriptional targets hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. Furthermore, autophagy induced by BBD contributed to hepatoprotection activity., Conclusions: Our results suggest that BBD can markedly dispel acute ethanol-induced hepatotoxicity through multiple pathways including attenuation of ethanol-mediated oxidative stress, enhancement of the oxidative defense systems and activation of autophagy., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Mercury (Hg) is generally considered as a toxic metal; yet the biological outcomes of Hg-containing compounds are highly dependent upon their chemical forms. We hypothesize that mercury sulfide (HgS) is different from HgCl 2 and methylmercury (MeHg) in producing intestinal Hg absorption and disruption of gut microbiome. To test this hypothesis, mice were given orally with HgS (α-HgS, 30 mg/kg), Zuotai (β-HgS, 30 mg/kg), HgCl 2 (33.6 mg/kg, equivalent Hg as HgS), or MeHg (3.1 mg/kg, 1/10 Hg as HgS) for 7 days. Accumulation of Hg in the duodenum and ileum after HgCl 2 (30-40 fold) and MeHg (10-15 fold) was higher than HgS and Zuotai (~2-fold). HgCl 2 and MeHg decreased intestinal intake peptide transporter-1 and Ost-β, and increased ileal bile acid binding protein and equilibrative nucleoside transporter-1. The efflux transporters ATP-binding cassette sub-family C member-4 (Abcc4), Abcg2, Abcg5/8, and Abcb1b were increased by HgCl 2 and to a lesser extent by MeHg, while HgS and Zuotai had minimal effects. Bacterial DNA was extracted and subjected to 16S rDNA sequencing. Operational taxonomic unit (OTU) results showed that among the 10 phyla, HgS increased Firmicutes, Proteobacteria, while HgCl 2 increased Bacteroidetes, Cyanobacteria and decreased Firmicutes; among the 79 families, HgS increased Rikenellaceae, Lactobacillaceae, Helicobacteraceae, and decreased Prevotellaceae, while HgCl 2 increased Odoribacteraceae, Porphyromonadaceae, and decreased Lactobacillaceae; among the 232 genus/species, HgS and Zuotai affected gut microbiome quite differently from HgCl 2 and MeHg. qPCR analysis with 16S rRNA confirmed sequencing results. Thus, chemical forms of mercury are a major determinant for intestinal Hg accumulation, alterations in transporters and disruption of microbiome., (Copyright © 2019. Published by Elsevier Inc.)

Metastasis and recurrence severely impact the treatment effect of hepatocellular carcinoma (HCC). HCC complicated with cholestasis is more prone to recurrence and metastasis. Previous studies have implicated pathogenesis of HCC by bile acid; however, the underlying mechanism is unknown yet. Glycochenodeoxycholate (GCDC) is one of most important component of bile acid (BA). In the present study, the role of GCDC in HCC cells invasion was detected by in vitro and in vivo assays. GCDC was found to significantly enhance the invasive potential of HCC cells; Further studies showed that GCDC could induce autophagy activation and higher invasive capability in HCC cells. Interestingly, inhibition of autophagy by chloroquine (CQ) reversed this phenomenon. Subsequently, the correlation between TBA expression level and clinicopathological characteristics was analyzed in HCC patients. Clinically, high TBA level in HCC tissue was found to be associated with more invasive and poor survival in HCC patients. Mechanistic study showed that bile acid induced autophagy by targeting the AMPK/mTOR pathway in HCC cells. Therefore, our results suggest that bile acid may promote HCC invasion via activation of autophagy and the level of bile acid may serve as a potential useful indicator for prognosis of HCC patients., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective To compare the impacts of different nostril on nasotracheal intubation with video laryngoscopy.Methods Totally 120 ASA grade I maxillofacial surgery patients were equally randomized into two groups:group A(left nostril)and group B(right nostril).After rapid induction of anesthesia,the nasal intubation was completed by Tosight video laryngoscope,and the success rate of the first attempt of the tube passing through the nasal cavity was recorded and compared between these two groups.In addition,time of tube through nasal cavity,time of glottis exposure,total intubation time,intubation success rate,and nasal bleeding were recorded.Results The success rate of the first attempt of tube passing through the nasal cavity was not significantly different between groups A and B(84.7% vs . 81.7%; χ 2 =0.202, P =0.653).The time of tube passing through nasal cavity [(7.3±4.6)s vs .(7.5±4.1)s; t =-0.223, P =0.824] and the time of glottic exposure [(6.6±1.4)s vs .(6.7±1.4)s; t =-0.348, P =0.728] had no significant differences between two groups.The success rates of first intubation attempt were 100% in both groups.The total intubation time was(35.1±9.2)s in group A and(34.0±7.8)s in group B( t =0.663, P =0.509).Intubation-related epistaxis was found in 16 cases(27.1%)in group A and in 17 cases(28.3%)in group B( χ 2 =0.022, P =0.882).Conclusion Different nasal approaches have no effect on nasal intubation.

Ethnopharmacological Relevance: Zuotai (gTso thal) has a long history in the treatment of cardiovascular disease, liver and bile diseases, spleen and stomach diseases as a precious adjuvant in Tibetan medicine. However, Zuotai is a mercury preparation that contains 54.5% HgS. Its application has always been controversial., Aim of the Study: To evaluate the toxicological effects of Zuotai in hepatocytes and in zebrafish., Materials and Methods: MTT was used to determine the survival rate of hepatocytes; Hoechst and TUNEL staining were used to detect the apoptosis cells; Western blot and RT-qPCR assay were used to determine the expression levels of the protein and mRNA; Liver morphology observation and H&E staining were used to evaluate the hepatotoxicity of Zuotai in Zebfrafish., Results: The survival rate of L-02 cells, HepG2 cells and RBL-2A cells reduced by Zuotai (10 -4 -0.1 mg/mL) in a dose and time-dependent manner. Zuotai (0.1 mg/mL) induced HepG2 cells shrinkage, condensation and fragmentation and increased the number of apoptosis cells. The protein expression levels of cleaved Caspase-3 and Bax were increased and the expression levels of Bcl-2 were reduced after HepG2 cells exposed to Zuotai (10 -4 -0.1 mg/mL) for 24 h. In addition, Zuotai (0.2 mg/mL) induced the darker liver color of the larval zebrafish and changed the liver morphologic of adult zebrafish. Zuotai (0.2 mg/mL) also increased the mRNA levels of CYP1A1, CYP1B1 and MT-1 in the liver of adult zebrafish. However, no significantly hepatotoxicity was observed after hepatocytes and zebrafish exposed to HgS at the same dose., Conclusions: Results showed that Zuotai induced hepatotoxicity effectively under a certain dose but its hepatotoxicity likely occurs via other mechanisms that did not depend on HgS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Minerals are alchemically processed as Bhasmas in Ayurvedic medicines or as Zuotai in Tibetan medicines. Ayurveda is a knowledge system of longevity and considers the mineral elixir made from "nature" capable of giving humans perpetual life. Herbo-metallic preparations have a long history in the treatment of various diseases in India, China, and around the world. Their disposition, pharmacology, efficacy, and safety require scientific evaluation. This review discusses the Bhasmas in Ayurvedic medicines and Zuotai in Tibetan medicines for their occurrence, bioaccessibility, therapeutic use, pharmacology, toxicity, and research perspectives. A literature search on Mineral, Bhasma, Ayurvedic medicine, Zuotai, Tibetan medicine, and Metals/metalloids from PubMed, Google and other sources was carried out, and the relevant papers on their traditional use, pharmacology, and toxicity were selected and analyzed. Minerals are processed to form Bhasma or Zuotai to alter their physiochemical properties distinguishing them from environmental metals. The metals found in Ayurveda are mainly from the intentional addition in the form of Bhasma or Zuotai. Bhasma and Zuotai are often used in combination with other herbals and/or animal-based products as mixtures. The advanced technologies are now utilized to characterize herbo-metallic preparations as Quality Assurance/Quality Control. The bioaccessibility, absorption, distribution, metabolism, and elimination of herbo-metallic preparations are different from environmental metals. The pharmacological basis of Bhasma in Ayurveda and Zuotai in Tibetan medicines and their interactions with drugs require scientific research. Although the toxic potentials of Bhasma and Zuotai differ from environmental metals, the metal poisoning case reports, especially lead (Pb), mercury (Hg), and arsenic (As) from inappropriate use of traditional medicines, are increasing, and pharmacovigilance is desired. In risk assessment, chemical forms of metals in Bhasma and Zuotai should be considered for their disposition, efficacy, and toxicity.

Global warming-associated increases in temperature, particularly at nighttime, are detrimental to rice yield and quality. Metabolomic profiling was used to examine and compare the short-term extreme high nighttime temperature-induced molecular perturbations in rice ( Oryza sativa) coisogenic strains with contrasting heat-tolerances at the first stage of seed ripening. Compared to the heat-sensitive strain, antioxidant molecules were higher in abundance in the heat-tolerant strain, whereas the abundances of molecules involved in photosynthesis, nucleotide catabolism, and the S-adenosylmethionine (SAM) cycle varied only slightly. Thus, we proposed that the high abundance of antioxidant molecules in the heat-tolerant strain alleviated cellular oxidative stress, which protected photosynthesis, nucleotide catabolism, and the SAM cycle, leading to good grain filling.

A variety of 2-aminobenzonitriles were prepared from 2-arylindoles in good to excellent yields through tert-butylnitrite (TBN)-mediated nitrosation and sequential iron(III)-catalyzed C-C Bond cleavage in a one-pot fashion. The 2-aminobenzonitriles can be used to rapidly synthesize benzoxazinones by intramolecular condensation. The present method features an inexpensive iron(III) catalyst, gram scalable preparations, and novel C-C bond cleavage of indoles.

Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are well-known leading causes of HCC. However, the mechanism of the induction of HCC by these virus is still being debated. This review will focus on the current knowledge of the pathogenesis of HBV- and HCV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC. It is well established that the recruitment of certain number and type of immune cells to liver is essential for the resolution of HBV and HCV infection and the prevention of subsequent chronic persistent infection. However, in case that the immune response do not completely clear virus, persistent chronic infection occurs, and the perpetual immune response may contribute to chronic damages of the liver. Such chronic inflammatory damages further harm hepatocytes, but not hepatic progenitor cells (HPCs). Thus, following chronic damages, HPCs are activated and their dysregulated proliferation ensures survival in the hostile environment, contributing to the tumorigenesis of HCC. Furthermore, accumulating evidence also provides a strong link between HPCs and human hepatocellular carcinoma. Collectively, these findings support a notion that immune response is involved in liver damage during hepatitis virus infection, and the activation and dysregulated differentiation of hepatic progenitor cells promote the tumorigenesis of human hepatocellular carcinoma., (Copyright © 2017. Published by Elsevier Inc.)

Ethnopharmocological Relevance: Herbo-metallic preparations have a long history in the treatment of diseases, and are still used today for refractory diseases, as adjuncts to standard therapy, or for economic reasons in developing countries., Aim of the Review: This review uses cinnabar (HgS) and realgar (As 4 S 4 ) as mineral examples to discuss their occurrence, therapeutic use, pharmacology, toxicity in traditional medicine mixtures, and research perspectives., Materials and Methods: A literature search on cinnabar and realgar from PubMed, Chinese pharmacopeia, Google and other sources was carried out. Traditional medicines containing both cinnabar and realgar (An-Gong-Niu-Huang Wan, Hua-Feng-Dan); mainly cinnabar (Zhu-Sha-An-Shen Wan; Zuotai and Dangzuo), and mainly realgar (Huang-Dai Pian; Liu-Shen Wan; Niu-Huang-Jie-Du) are discussed., Results: Both cinnabar and realgar used in traditional medicines are subjected to special preparation procedures to remove impurities. Metals in these traditional medicines are in the sulfide forms which are different from environmental mercurials (HgCl 2 , MeHg) or arsenicals (NaAsO 2 , NaH 2 AsO 4 ). Cinnabar and/or realgar are seldom used alone, but rather as mixtures with herbs and/or animal products in traditional medicines. Advanced technologies are now used to characterize these preparations. The bioaccessibility, absorption, distribution, metabolism and elimination of these herbo-metallic preparations are different from environmental metals. The rationale of including metals in traditional remedies and their interactions with drugs need to be justified. At higher therapeutic doses, balance of the benefits and risks is critical. Surveillance of patients using these herbo-metallic preparations is desired., Conclusion: Chemical forms of mercury and arsenic are a major determinant of their disposition, efficacy and toxicity, and the use of total Hg and As alone for risk assessment of metals in traditional medicines is insufficient., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Defects of the growth arrest DNA damage-inducible gene 45β (Gadd45β) play an important role in the progression of tumor and confer resistance to chemotherapy. However, the role of Gadd45β in the apoptosis of hepatocellular carcinoma is still not clear. Purpose of this study was to explore the effect of Gadd45β on the apoptosis of liver cancer cells, and the possible mechanism was examined., Result: In this study, we first confirmed the decreased expression of Gadd45β in human liver cancer tissues and human liver cancer cell lines, when compared to the peri-tumor liver tissue and normal liver cells. And, it was found that Gadd45β could inhibit the stemness of liver cancer cells, enhancing the apoptosis of cancer cells induced by chemotherapy. Furthermore, the results showed that HCC tissues and cell lines showed a higher methylation status in Gadd45β promoter than that in peri-tumor tissues and normal liver cells. Methylation was then reversed by pretreatment of SMMC-7721 and Hep-3B with 5-azacytidine which is the DNA methyltransferase inhibitor. And the 5-azacytidine decreased the stemness of SMMC-7721 and Hep-3B, enhanced the sensitivity of SMMC-7721 and Hep-3B to cisplatin., Conclusions: Methylation mediated Gadd45β expression inhibited the stemness of liver cancer cells, promoting the chemotherapy-induced apoptosis. Thus Gadd45β may be the potential target for enhancing the chemosensitivity of human hepatocellular carcinoma.

Thyroid cancer is the most common type of malignant endocrine tumor diagnosed. Previous studies have indicated that gene therapy is the most promising and effective therapeutic method for thyroid cancer. Therefore, in the present study, Na 131 I/5-fluorocytosine (5-FC) treatment was combined with cytosine deaminase (CD, encoded by the CDA gene) and sodium iodide symporter (NIS, encoded by the SLC5A5 gene) to act together as a therapeutic tool for thyroid cancer. The present study explored the combined cytotoxic effects of adenovirus-mediated CD and NIS under the control of the progression elevated gene-3 ( PEG-3 ) promoter (Ad-PEG-3-CD-NIS) with Na 131 I/5-FC against the human thyroid cancer TT cell line in vitro . The PEG-3 fragment was obtained by polymerase chain reaction (PCR) using rat genomic DNA as the template, and then Ad- PEG-3-CDA-SLC5A5 was constructed using Xba I. TT cells were transfected by recombinant adenovirus. The method of reverse transcription-quantitative PCR was performed to test the expression of CD and NIS at the level of transcription. The morphological change was assessed by fluorescence microscopy and investigated by western blot analysis. An MTT assay was used to determine the number of living cells inhibited by single or combination therapies on TT cells. The results indicated that the PEG-3 was successfully cloned, and was also positively regulated in 293 cells. CDA and SLC5A5 genes were highly expressed in TT cells. Na 131 I combined with 5-FC significantly decreased the human thyroid cancer cells. In conclusion, combination therapy of Ad- PEG3-CDA-SLC5A5 and Na 131 I/5-FC induces significantly more apoptotic characteristics than either single treatment with Ad- PEG-3-CDA-SLC5A5 or Na 131 I/5-FC, and low doses of Ad- PEG-3-CDA-SLC5A5 enhanced the cytotoxic effects.

Combined hepatocellular-cholangiocarcinoma (CHC) is a mixed tumor containing elements of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Its remarkable histological heterogeneity has been linked to putative hepatic progenitor cell (HPC) origin. However, detailed histological or phenotypic description is rarely documented. In the present study, we reassessed 68 cases previously diagnosed as hepatitis B-related CHCs by immunohistochemistry and double-fluorescence immunostaining, focusing on HPC associated phenotypic observation of intermediate area of the tumor. It was found that tumor cells showed remarkable heterogeneity in intermediate area. Tumor cells with intermediate morphology between hepatocytes and cholangiocytes were oval-shaped and small with scant cytoplasm and hyperchromatic nuclei, arranging in solid nests mostly. By Keratin 7 (K7) staining, it appeared that the nests of tumor cells represented a maturation process from the undifferentiated small cells to mature hepatocytes through the "transitional" cells. Then, these small cells were further confirmed with intermediate phenotype as HPC by exploring immature hepatocellular marker and HPC/biliary markers co-localization. In conclusion, the HPC associated trait in CHC can be interpreted by HPC origin or gain of "stemness" by dedifferentiation. It is still too soon to give a final word that it is innate or acquired signature of HPC associated trait in CHC.

Zuotai and cinnabar(96%HgS) are contained in many traditional medicines. To examine their potential effects on drug metabolism genes, mice were orally given Zuotai or HgS at doses of 10, 30, 100, 300 mg•kg⁻¹ for 7 days. HgCl2(33.6 mg•kg⁻¹) was gavaged for control. Twenty-four hour later after the last administration, livers were collected, and expressions of genes related to metabolic enzymes and transporters were examined. Zuotai and HgS had no effects on major phase-1, phase-2 and transporter genes; HgCl2 increased the expressions of CYP2B10, CYP4A10, OATP1A4, UGT1A1, UGT2A3, SULT1A1, SULT2A1, MRP1, MRP3 and MRP4; expression of OATP1A1 was decreased by HgCl2, but not by Zuotai and HgS. Therefore, Zuotai and HgS have different adverse effects on drug-metabolizing genes from HgCl2., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Mercury sulfides are used in Ayurvedic medicines, Tibetan medicines, and Chinese medicines for thousands of years and are still used today. Cinnabar (α-HgS) and metacinnabar (β-HgS) are different from mercury chloride (HgCl 2 ) and methylmercury (MeHg) in their disposition and toxicity. Whether such scenario applies to weanling and aged animals is not known. To address this question, weanling (21d) and aged (450d) rats were orally given Zuotai (54% β-HgS, 30mg/kg), HgS (α-HgS, 30mg/kg), HgCl 2 (34.6mg/kg), or MeHg (MeHgCl, 3.2mg/kg) for 7days. Accumulation of Hg in kidney and liver, and the toxicity-sensitive gene expressions were examined. Animal body weight gain was decreased by HgCl 2 and to a lesser extent by MeHg, but unaltered after Zuotai and HgS. HgCl 2 and MeHg produced dramatic tissue Hg accumulation, increased kidney (kim-1 and Ngal) and liver (Ho-1) injury-sensitive gene expressions, but such changes are absent or mild after Zuotai and HgS. Aged rats were more susceptible than weanling rats to Hg toxicity. To examine roles of transporters in Hg accumulation, transporter gene expressions were examined. The expression of renal uptake transporters Oat1, Oct2, and Oatp4c1 and hepatic Oatp2 was decreased, while the expression of renal efflux transporter Mrp2, Mrp4 and Mdr1b was increased following HgCl 2 and MeHg, but unaffected by Zuotai and HgS. Thus, Zuotai and HgS differ from HgCl 2 and MeHg in producing tissue Hg accumulation and toxicity, and aged rats are more susceptible than weanling rats. Transporter expression could be adaptive means to reduce tissue Hg burden., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective To investigate the effect of intravenous dexmedetomidine injection(1 μg/kg)on the intubating conditions after inhalation induction with sevoflurane 8% and nitrous oxide(N 2 O)50% in children. Methods Totally 122 patients aged 4-10 years with an American Society of Anesthesiologists physical statusⅠ undergoing elective plastic surgery under general anesthesia were randomly divided to dexmedetomidine group(intraveneously injected with dexmedetomidine 1μg/kg)and control group(injected with normal saline)by using the random sampling table.On arrival of the operating room,anesthesia was induced with sevoflurane 8% and N 2 O 50% in oxygen 50%.When the patient became unconscious,the intravenous cannula 24 # was inserted on the dorsum of hand.One minute later,laryngoscopy and tracheal intubation were performed.The intubating conditions were assessed by the scoring system in the previous study. Results The rates of acceptable conditions were 97% and 90% in dexmedetomidine group and in control group(P=0.143),and the rates of excellent conditions were 82% and 67%(P=0.04),respectively.In dexmedetomidine group,there were no signifi-cant differences of mean arterial presser and heart rate between the time-point of before intubation and the time-point of immediately after intubation.Conclusion Intravenous bolus of dexmedetomidine(1 μg/kg)can effectively improve the intubating conditions after inhalation induction of sevoflurane 8% and N 2 O 50% in children and make the hemodynamics more stable during tracheal intubation.

Tumor protein p53 has been intensively studied as a major tumor suppressor. The activation of p53 is associated with various anti-neoplastic functions, including cell senescence, cell cycle arrest, apoptosis and inhibition of angiogenesis. However, the role of p53 in cancer cell chemosensitivity remains unknown. Cholangiocarcinoma cell lines QBC939 and RBE were grown in full-nutrient and nutrient-deprived conditions. The cell lines were treated with 5-fluorouracil or cisplatin and the rate of cell death was determined in these and controls using Cell Counting Kit-8 and microscopy-based methods, including in the presence of autophagy inhibitor 3MA, p53 inhibitor PFT-α or siRNA against p53 or Beclin-1. The present study demonstrated that the inhibition of p53 enhanced the sensitivity to chemotherapeutic agents in nutrient-deprived cholangiocarcinoma cells. Nutrient deprivation-induced autophagy was revealed to be inhibited following inhibition of p53. These data indicate that p53 is important for the activation of autophagy in nutrient-deprived cholangiocarcinoma cells, and thus contributes to cell survival and chemoresistance.

Normally, hepatic progenitor cells (HPCs) are activated and differentiate into hepatocytes or bile ductular cells to repair liver damage during liver injury. However, it remains controversial whether the abnormal differentiation of HPCs occurs under abnormal conditions. Lipopolysaccharide (LPS), a component of the microenvironment, promotes liver fibrosis. In the present study, HPCs promoted liver fibrosis in rats following carbon tetrachloride (CCl 4 ) treatment. Meanwhile, the LPS level in the portal vein was elevated and played a primary role in the fate of HPCs. In vitro, LPS inhibited the hepatobiliary differentiation of HPCs. Concurrently, HPCs co-cultured with LPS for 2 weeks showed a tendency to differentiate into myofibroblasts (MFs). Thus, we conclude that LPS promotes the aberrant differentiation of HPCs into MFs as a third type of descendant. This study provides insight into a novel differentiation fate of HPCs in their microenvironment, and could thus lead to the development of HPCs for treatment methods in liver fibrosis.