bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clock gene Bmal1 controls diurnal rhythms in expression and activity of intestinal carboxylesterase 1
Authors: Chen Xun , Yu Fangjun , Guo Xiaolei , Su Chong , Li Shu-Shu , Wu Baojian 
Published: January 2021

Abstract

Objectives
We aimed to characterize diurnal rhythms in CES1 expression and activity in mouse intestine, and to investigate a potential role of the core clock gene Bmal1 in generating diurnal rhythms.

Methods
The regulatory effects of intestinal Bmal1 on diurnal CES1 expression were assessed using intestine-specific Bmal1 knockout (Bmal1iKO) mice and colon cancer cells. The relative mRNA and protein levels were determined by qPCR and Western blotting, respectively. Metabolic activity of CES1 in vitro and in vivo were determined by microsomal assays and pharmacokinetic studies, respectively. Transcriptional gene regulation was investigated using luciferase reporter assay.

Key findings
Total CES1 protein varied significantly according to time of the day in wild-type (Bmal1fl/fl) mice, peaking at ZT6. Of detectable Ces1 genes, Ces1d mRNA displayed a robust diurnal rhythm with a peak level at ZT6, whereas mRNAs of Ces1e, 1f and 1g showed no rhythms in wild-type mice. Loss of intestinal Bmal1 reduced the levels of total CES1 protein and Ces1d mRNA, and blunted their diurnal rhythms in mice. In vitro microsomal assays indicated that intestinal metabolism of mycophenolate mofetil (MMF, a known CES1 substrate) was more extensive at ZT6 than at ZT18. ZT6 dosing of MMF to wild-type mice generated a higher systemic exposure of mycophenolic acid (the active metabolite of MMF) as compared with ZT18 dosing. Intestinal ablation of Bmal1 down-regulated CES1 metabolism at ZT6, and abolished its time-dependency both in vitro and in vivo. Furthermore, Ces1d/CES1 rhythmicity and positive regulation of Ces1d/CES1 by BMAL1 were confirmed in CT26 and Caco-2 cells. Mechanistically, BMAL1 trans-activated Ces1d/CES1 probably via binding to the E-box elements in the gene promoters.

Conclusions
Bmal1 controls diurnal rhythms in expression and activity of intestinal CES1. Our findings have implications for understanding the crosstalk between circadian clock and xenobiotic metabolism in the intestine.
Scrophularia ningpoensis Hemsl: a review of its phytochemistry, pharmacology, quality control and pharmacokinetics
Authors: Zhang Qing , Liu An , Wang Yuesheng 
Published: January 2021

Abstract

Objectives
Scrophularia ningpoensis Hemsl (SNH) is a commonly used medicinal plant in East Asia. Scrophulariae Radix (SR) is the dried roots of SNH, and is one of the most commonly used medicinal parts of SNH, and is an essential traditional medicine and widely used in East Asia for more than 2000 years. SR is used for clearing away heat and cooling blood, nourishing Yin and reducing fire, detoxicating and resolving a mass. The purpose of this paper is to systematically review the phytochemistry, pharmacology, quality control and pharmacokinetics of SNH based on the surveyed and summarized literature.

Key ﬁndings
Up to now, iridoids, phenolic glycosides, phenolic acids, alkaloids, flavonoids, triterpenes and other compounds have been isolated and identified from SNH. The extract and chemical components of SNH exerts multiple pharmacological effects, such as hepatoprotective effect, anti-inflammatory effect, neuroprotective effect, anti-ventricular remodeling effect and other activities. Various methods have been developed for the quality control of SNH, mainly for SR. Some bioactive compounds in SNH exhibited different pharmacokinetic behaviours and individual metabolic transformation profiles.

Summary
This review will contribute to understanding the correlation between the pharmacological activities and the traditional usage of SNH, and useful to rational use and drug development in the future.
Oral drug delivery systems using core–shell structure additive manufacturing technologies: a proof-of-concept study
Authors: Zhang Jiaxiang , Xu Pengchong , Vo Anh Q , Repka Michael A 
Published: January 2021

Abstract

Objectives
The aim of this study was to couple fused deposition modelling 3D printing with melt extrusion technology to produce core–shell-structured controlled-release tablets with dual-mechanism drug-release performance in a simulated intestinal fluid medium. Coupling abovementioned technologies for personalized drug delivery can improve access to complex dosage formulations at a reasonable cost. Compared with traditional pharmaceutical manufacturing, this should facilitate the following: (1) the ability to manipulate drug release by adjusting structures, (2) enhanced solubility and bioavailability of poorly water-soluble drugs and (3) on-demand production of more complex structured dosages for personalized treatment.

Methods
Acetaminophen was the model drug and the extrusion process was evaluated by a series of physicochemical characterizations. The geometries, morphologies, and in vitro drug-release performances were compared between directly compressed and 3D-printed tablets.

Key findings
Initially, 3D-printed tablets released acetaminophen more rapidly than directly compressed tablets. Drug release became constant and steady after a pre-determined time. Thus, rapid effectiveness was ensured by an initially fast acetaminophen release and an extended therapeutic effect was achieved by stabilizing drug release.

Conclusions
The favourable drug-release profiles of 3D-printed tablets demonstrated the advantage of coupling HME with 3D printing technology to produce personalized dosage formulations.
Steroidal saponins from Trillium govanianum as α-amylase, α-glucosidase, and dipeptidyl peptidase IV inhibitory agents
Authors: Suresh Patil Shivprasad , Singh Prithvi Pal , Padwad Yogendra S , Sharma Upendra 
Published: January 2021

Abstract

Objective
To provide the scientific basis for the utility of rhizome of Trillium govanianum as nutraceutical supplements in managing physiological glycemic levels.

Methods
The in vitro enzyme inhibitory activity of the extract, fractions, and the isolated steroidal saponins from the rhizome part of T. govanianum was carried out against α-amylase, α-glucosidase, and dipeptidyl peptidase IV. The molecular interactions, binding score, and pharmacokinetic parameters (absorption, distribution metabolism, and excretion) of steroidal saponins were analyzed by the Schrodinger molecular docking software.

Key findings
Current study explained that the extract, fractions, and isolated steroidal saponins from T. govanianum possess good α-amylase and α-glucosidase inhibitory activity while moderate dipeptidyl peptidase IV inhibitory activity. Moreover, in vitro results revealed that borassoside E (IC50 7.15 ± 1.78 μM), protodioscin (IC50 6.72 ± 0.04 μM), and diosgenin (IC50 12.75 ± 2.70 μM) are most effective in inhibiting the activity of α-amylase, α-glucosidase, and dipeptidyl peptidase IV, respectively. Current in silico and in vitro studies established an association between the steroidal saponins from T. govanianum and their molecular interactions with α-amylase, α-glucosidase, and dipeptidyl peptidase IV.

Conclusion
The results of this investigation suggest that fractions and steroidal saponins from T. govanianum exhibit good antidiabetic activity which could be used as nutraceutical supplements for the management of systemic glucose level.
Effects of minocycline on motor function recovery and expression of glial fibrillary acidic protein and brain-derived neurotrophic factor after spinal cord injury in rats
Authors: Xu Jiancheng , Ji Jing , Wang Zhan , Xu Tao 
Published: January 2021

Abstract

Objectives
Study explore the effects of minocycline on the expression of glial fibrillary acidic protein and brain-derived neurotrophic factor after spinal cord injury and its possible mechanism of action.

Methods
The model of acute spinal cord injury was established by Allen’s method. The rats in each group were assessed with Basso Beattie Bresnahan score of hindlimb motor function and inclined plate test score. Serum malondialdehyde and superoxide dismutase, glial fibrillary acidic protein and brain-derived neurotrophic factor in spinal cord were compared.

Key findings
Basso Beattie Bresnahan scores, Tiltboard experiment max angles, and Serum superoxide dismutase activity of the minocycline group were higher than those of the model group after surgery (P &lt; 0.05). Serum malondialdehyde content, and expression of the minocycline group was lower than that of the model group (P &lt; 0.05), and brain-derived neurotrophic factorexpression of minocycline group was significantly higher in the model group after surgery (P &lt; 0.05). Minocycline can promote the recovery of motor function after spinal cord injury in rats.

Conclusions
The mechanism of action may be that it inhibits local free radical generation, reduces lipid peroxidation and glial fibrillary acidic protein expression in spinal cord tissue after spinal cord injury, and promotes the synthesis of endogenous brain-derived neurotrophic factor, thus improving the microenvironment of spinal cord regeneration after spinal cord injury in rats.
Paeoniflorin modulates oxidative stress, inflammation and hepatic stellate cells activation to alleviate CCl4-induced hepatic fibrosis by upregulation of heme oxygenase-1 in mice
Authors: Wang Ting , Zhou Xu , Kuang Ge , Jiang Rong , Guo Xinyi , Wu Shengwang , Wan Jingyuan , Yin Liangjun 
Published: January 2021

Abstract

Objectives
The role of Paeoniflorin on hepatic fibrosis and the specific mechanisms has not yet been elucidated. Therefore, we explored whether Paeoniflorin exerted protective effects on carbon tetrachloride (CCl4)-induced hepatic fibrosis and the underlying mechanisms.

Methods
A model of hepatic fibrosis was induced by intraperitoneally injecting with CCl4 (10% 5 μl/g) twice a week for 7 weeks. To explore the effects of Paeoniflorin, mice were treated with Paeoniflorin (100 mg/kg) by gavage once a day at 1 week after modeling until they were sacrificed.

Key findings
Paeoniflorin remarkably improved liver function and histopathological changes of hepatic tissues in CCl4-induced liver injury. Besides, the serum MAO enzyme activity and hydroxyproline contents were notably decreased following the intervention of Paeoniflorin. The decreased expression of Vimentin, α-SMA, Col1a and Desmin manifested the inhibition of the hepatic stellate cells (HSCs) activation. Interestingly, Paeoniflorin intervention significantly upregulated the expression of heme oxygenase-1, and attenuated the inflammatory cytokines production as well as the CCl4-induced oxidative stress imbalance.

Conclusions
Paeoniflorin could effectively alleviate CCl4-induced hepatic fibrosis by upregulation of heme oxygenase-1, and it might be a new effective option for the comprehensive treatment of hepatic fibrosis.
Antiviral activity against Zika virus of a new formulation of curcumin in poly lactic-co-glycolic acid nanoparticles
Authors: Pacho María Natalia , Pugni Eugenio Nahuel , Díaz Sierra Johanna Briyith , Morell María Laura , Sepúlveda Claudia Soledad , Damonte Elsa Beatriz , García Cybele Carina , D’Accorso Norma Beatriz 
Published: January 2021

Abstract

Objectives
In the search of an effective antiviral formulation, the natural product curcumin (CUR) was encapsulated into poly(lactic-co-glycolic acid) nanoparticles, a non-toxic bioresorbable and biocompatible copolymer. The resulting CUR containing particles (PLGA-CUR NPs) were characterized and analysed for antiviral activity against Zika virus (ZIKV) infection.

Methods
The PLGA-CUR NPs were characterized by Fourier transform infrared, differential scanning calorimetry, dynamic light scattering, scanning electron microscopy and thermogravimetric analysis and release profile. Cytotoxicity of PLGA-CUR and the antiviral activity against ZIKV were determined in Vero cells. The effect of PLGA-CUR NPs on viral RNA synthesis and protein expression was analysed by RT–qPCR and immunofluorescence staining, respectively.

Key findings
The PLGA-CUR NPs showed an appropriate in vitro drug release profile. Our studies of the antiviral activity of PLGA-CUR NPs and CUR against ZIKV by virus yield reduction as well as viral RNA synthesis and protein expression have shown that PLGA-CUR formulation is more effective than free CUR to inhibit ZIKV infection of Vero cells.

Conclusions
Our results demonstrate for the first time the antiviral activity against ZIKV of PLGA nanoparticles charged with CUR, suggesting that PLGA-CUR NPs are promising candidates for a drug formulation against human pathogenic flaviviruses.
The role of lncRNA ANRIL in the progression of hepatocellular carcinoma
Authors: Han Weijie , Wang Qiuhong , Zheng Liansheng , Hong Hong , Yan Boshi , Ma Yongqiang , Li Xiaolong , Zhou Dinghua 
Published: January 2021

Abstract

Objectives
The aim of the current study was to identify the long noncoding RNAs (lncRNAs) ANRIL function and molecular pathways underlying hepatocellular carcinoma progression.

Methods
ANRIL knockdown with specific siRNA, and transfected into HepG2 cells according to the protocol of Lipofectamine 2000. Cell proliferation, apoptosis, migration and metastasis were assessed with MTT assay, flow cytometry and wound healing assay, respectively. Moreover, the expression level of ANRIL, apoptosis-related genes, and the Wnt pathway-associated genes were assessed by real time-PCR and Western blot assay.

Key findings
Knocking down of ANRIL led to alleviated cell growth and increased cell apoptosis of HepG2 cells through markedly increased expression levels of Bax and Bad. In contrast, dramatically diminished the expressions of anti-apoptotic factors including Bid and Bcl-2 in comparison to the scrambled control group (si-NC). Furthermore, ANRIL silencing resulted in an inactivated Wnt/β-catenin pathway by suppressing key genes associated with this pathway.

Conclusions
Taken together, these findings imply new insights into the regulatory network of the Wnt pathway through lncRNA ANRIL that indicate ANRIL may be a therapeutic factor potential for hepatocellular carcinoma.
Phosphatidylinositol 3-kinase gamma participates in nimesulide-induced hepatic damage
Authors: Pereira Cynthia Maria C , Júnior Genilson José Dias , Lima José Victor do N , Alves Lemos Sarah Izabelly , da Rocha Rodrigues Lauanda , dos Santos Ferreira Jayro , Araújo Anna Sofia Miranda Loiola , de Oliveira Joveline Costa , Monteiro Carlos Eduardo , Franco Álvaro Xavier , Pereira Alves Even Herlany , Oliveira Silva Francisca Géssica , de Carvalho Filgueiras Marcelo , Soares Pedro M G , Pereira Vasconcelos Daniel Fernando , de Oliveira Jefferson Soares , de Brito Tarcisio Vieira , Barbosa André Luiz Reis 
Published: January 2021

Abstract

Objective
To evaluate the participation of the phosphatidylinositol 3-kinase pathway in the liver damage caused by nimesulide.

Methods
Liver damage been induced by nimesulide. Mice were treated with either 2% dimethyl sulfoxide or AS605240, a phosphatidylinositol 3-kinase gamma pathway antagonist. Blood samples were collected for function assays of liver. The liver was removed for analysis of liver weight/animal weight ratio, histopathological parameters, oxidative and nitrous stress, cytokine levels, and the immunostaining for cyclooxygenase 2 and nuclear factor kappa B.

Key findings
Liver injured by nimesulide and treated with phosphatidylinositol 3-kinase gamma inhibitor significantly reversed (P &lt; 0.05) the damage; it decreased the liver weight/animal weight ratio, histopathological scores, and neutrophil infiltration, consequently reducing oxidative stress. In addition, we show that phosphatidylinositol 3-kinase gamma is associated with hepatic damage induced by nimesulide, because it altered liver function and increased the protein immunostaining of cyclooxygenase 2 and nuclear factor kappa B in the liver tissue of nimesulide-treated animals.

Conclusions
The findings from the present study allows us to infer that nimesulide causes liver damage through the phosphatidylinositol 3-kinase gamma pathway.
The antiproliferative effects of ataxia-telangiectasia mutated and ATM- and Rad3-related inhibitions and their enhancements with the cytotoxicity of DNA damaging agents in cholangiocarcinoma cells
Authors: Moolmuang Benchamart , Ruchirawat Mathuros 
Published: January 2021

Abstract

Objective
To investigate whether the inhibitions of ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases by their specific inhibitors, KU-55933 and VE-821, respectively, are able to promote the cytotoxic activity of genotoxic agents including gemcitabine, 5-Fluorouracil, cisplatin and doxorubicin, in cholangiocarcinoma (CCA) and immortalized cholangiocyte cell lines.

Methods
Cell viability of cells treated with DNA damaging agents, alone and in combination with KU-55933 and VE-821, was determined by MTT assay. The changes of cell cycle distribution were evaluated by flow cytometry analysis. Colony formation was conducted to assess the effects of KU-55933 and VE-821 on cell proliferation. The levels of protein expression and phosphorylation were examined by western blot analysis.

Key findings
The cytotoxic effects of DNA damaging agents varied among CCA cell lines. Each DNA damaging drug induced different phases of the cell cycle in CCA cells. The combinations of both KU-55933 and VE-821 with DNA damaging agents promoted more cytotoxic activity than single inhibition in some CCA cell lines. ATM and ATR inhibitors decreased the effects of DNA damaging agent-induced ATM-Chk2 and ATR-Chk1 activations in CCA cells.

Conclusions
Inhibitions of ATM and ATR potentiated the cytotoxic effects of DNA damaging agents in CCA cells, especially p53 defective HuCCA1 and RMCC1 cell lines.
β-Cyclodextrin-containing chitosan-oligonucleotide nanoparticles improve insulin bioactivity, gut cellular permeation and glucose consumption
Authors: Wong Chun Yuen Jerry , Al-Salami Hani , Dass Crispin R 
Published: January 2021

Abstract

Objectives
The main objective of the present study was to develop a nanoparticulate drug delivery system that can protect insulin against harsh conditions in the gastrointestinal (GI) tract. The effects of the following employed techniques, including lyophilisation, cross-linking and nanoencapsulation, on the physicochemical properties of the formulation were investigated.

Methods
We herein developed a nanocarrier via ionotropic gelation by using positively charged chitosan and negatively charged Dz13Scr. The lyophilised nanoparticles with optimal concentrations of tripolyphosphate (cross-linking agent) and β-cyclodextrin (stabilising agent) were characterised by using physical and cellular assays.

Key findings
The addition of cryoprotectants (1% sucrose) in lyophilisation improved the stability of nanoparticles, enhanced the encapsulation efficiency, and ameliorated the pre-mature release of insulin at acidic pH. The developed lyophilised nanoparticles did not display any cytotoxic effects in C2C12 and HT-29 cells. Glucose consumption assays showed that the bioactivity of entrapped insulin was maintained post-incubation in the enzymatic medium.

Conclusions
Freeze-drying with appropriate cryoprotectant could conserve the physiochemical properties of the nanoparticles. The bioactivity of the entrapped insulin was maintained. The prepared nanoparticles could facilitate the permeation of insulin across the GI cell line.
Sorafenib suppresses proliferation rate of fibroblast-like synoviocytes through the arrest of cell cycle in experimental adjuvant arthritis
Authors: Gong YongFang , Huang TianYu , Yu QiRui , Liu Biao , Wang Jing , Wang ZhenHuan , Huang XueYing 
Published: January 2021

Abstract

Objectives
Rheumatoid arthritis, a recurrent incendiary autoimmune joint syndrome, features by prominent synovial hyperplasia. Fibroblast-like synoviocytes are the executive components in the pathogenesis of rheumatoid arthritis. It is generally accepted that excessive proliferation and reduced apoptosis of fibroblast-like synoviocytes lead to synovial hyperplasia. Our previously studies found that sorafenib could inhibit adjuvant arthritis in rats and induced adjuvant arthritis fibroblast-like synoviocytes apoptosis. Presently, we aim to investigate the inhibitory effect with mechanisms of action of sorafenib on adjuvant arthritis fibroblast-like synoviocytes proliferation.

Methods
Cell counting kit-8 and flow cytometry detection were conducted to monitor FLSs proliferation and cell cycle. Western blotting and qPCR assays were performed to detect P21, P53, CDK4, CyclinD1 and proliferating cell nuclear antigen content levels.

Key findings
Sorafenib significantly inhibited adjuvant arthritis fibroblast-like synoviocytes proliferation with an IC50 value of 4 µmol/L by a concentration-dependent pattern, which accompanies by G1 cell cycle arrest. Also, sorafenib significantly decreased the levels of P21, CyclinD1, CDK4 and proliferating cell nuclear antigen, as well as up-regulated P53 expression in adjuvant arthritis fibroblast-like synoviocytes.

Conclusions
Sorafenib could inhibit adjuvant arthritis fibroblast-like synoviocytes proliferation via arresting G1/S cell cycle progression, which was partially through CDK4/CyclinD1-mediated pathway, as well as up-regulating P53 and down-regulating proliferating cell nuclear antigen expressions. These results suggest that sorafenib may provide a new paradigm for rheumatoid arthritis treatment.
Research progress regarding potential effects of traditional Chinese medicine on postoperative intestinal obstruction
Authors: Wang Dan , Zhao Rong , Duan Hu-Xinyue , Zhang Meng-Meng , He Lin , Ye Xun , Wei Da-Neng , Wu Chun-Jie 
Published: January 2021

Abstract

Objectives
Postoperative intestinal obstruction is a common postoperative complication with typical symptoms of abdominal pain, vomiting, abdominal distension and constipation. The principal aim of this paper is to provide a full-scale review on the categories and characteristics of postoperative intestinal obstruction, pathophysiology, effects and detailed mechanisms of compounds and monomers from traditional Chinese medicine for treating postoperative intestinal obstruction. Moreover, the possible development and perspectives for future research are also analyzed.

Methods
Literature regarding postoperative intestinal obstruction as well as the anti-pio effect of aqueous extracts and monomers from traditional Chinese medicine in the last 20 years was summarized.

Key findings
To date, approximately 30 compounds and 25 monomers isolated from traditional Chinese medicine including terpenes, alkaloids, polysaccharides, flavonoids, phenylpropanoids and quinones, have exerted significant antipio effect. This paper reviews the effective doses, models, detailed mechanisms, and composition of these traditional Chinese medicine compounds, as well as the structure of these monomers. Moreover, challenges existed in the current investigation and further perspectives were discussed as well, hoping to provide a reference for future clinical treatment of postoperative intestinal obstruction and the development of new drugs.

Conclusions
Above all, the convincing evidence from modern pharmacology studies powerfully supported the great potential of traditional Chinese medicine in the management of postoperative intestinal obstruction. Regrettably, less attention was currently paid on the mechanisms of traditional Chinese medicine compounds and monomers with antipio effect. Consequently, future study should focus on monomer-mechanism and structure–function relationship.