Publications by authors named "Yu Yang"

4,594 Publications

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Correction to Copper-Catalyzed Asymmetric Hydrosilylation of β-Nitroethyl Aryl Ketones.

Org Lett 2021 Apr 13. Epub 2021 Apr 13.

Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen 510855, People's Republic of China.

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http://dx.doi.org/10.1021/acs.orglett.1c01119DOI Listing
April 2021

The effect of different dietary levels of sodium and chloride on performance, blood parameters and excreta quality in goslings at 29 to 70 days of age.

J Anim Physiol Anim Nutr (Berl) 2021 Apr 12. Epub 2021 Apr 12.

Yangzhou University, Yangzhou, China.

The purpose of this study was to ascertain the appropriate levels of dietary sodium (Na ) and chloride (Cl ) for 29- to 70-day-old goslings and to investigate the effects of different levels of Na and Cl on the growth performance, water consumption, blood parameters and excreta quality of goslings to provide a reference for the healthy production of goslings. In Experiment 1, a total of 432 29-day-old male Jiangnan White goslings were randomly allotted to nine treatments according to a 3 × 3 factorial design, with six pens containing eight birds per treatment. The goslings were fed diets with three concentrations of Na (0.10%, 0.15% and 0.20%) and three concentrations of Cl (0.15%, 0.20% and 0.25%). The experimental period was 42 days. In Experiment 2, a total of 24 70-day-old Jiangnan White goslings were selected for four treatments (0.10% Na  × 0.15% Cl ; 0.10% Na  × 0.25% Cl ; 0.20% Na  × 0.15% Cl and 0.20% Na  × 0.25% Cl ) and housed separately in metabolic cages. The faeces were collected for 3 consecutive days. In Experiment 1, the average daily feed intake (ADFI), average daily gain (ADG) and feed/gain (F/G) ratio of goslings were unaffected by the treatments. However, low levels of Na and Cl significantly reduced the water consumption of goslings in the later growth period (p < 0.05). The average water consumption of goslings fed with 0.10% Na  × 0.15% Cl was significantly lower than that of the goslings fed with 0.20% Na  × 0.25% Cl (56 days, 1304.2 ml vs. 1471.7 ml; 63 days, 1452.8 ml vs. 1610.8 ml; 70 days, 1540.0 ml vs. 1775.4 ml; p < 0.05). The interaction between Na and Cl (Na  × Cl ) had a significant impact on the blood haemoglobin (HGB) and haematocrit (HCT) levels in the goslings (p < 0.05). HGB increased linearly with increasing levels of Na . HGB and HCT first increased and then decreased with increasing levels of Cl . In Experiment 2, Na and Cl levels had significant effects on the excreta moisture content (p < 0.05). Goslings fed with 0.10% Na  × 0.15% Cl had a low moisture content of 5.58% compared to the goslings fed with 0.20% Na  × 0.25% Cl (87.51% vs. 93.09%; p < 0.05). The levels of dietary Na had a significant effect on the retention ratio of Na (p < 0.05), with the value for the 0.20% Na group being significantly higher than that for the 0.10% Na group (p < 0.05). In summary, different levels of Na and Cl did not affect the growth of goslings. To reduce the water consumption and moisture content of excreta, the Na and Cl levels in the diet can be as low as 0.10% and 0.15%, respectively.
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http://dx.doi.org/10.1111/jpn.13541DOI Listing
April 2021

Mechanisms restraining break-induced replication at two-ended DNA double-strand breaks.

EMBO J 2021 Apr 12:e104847. Epub 2021 Apr 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

DNA synthesis during homologous recombination is highly mutagenic and prone to template switches. Two-ended DNA double-strand breaks (DSBs) are usually repaired by gene conversion with a short patch of DNA synthesis, thus limiting the mutation load to the vicinity of the DSB. Single-ended DSBs are repaired by break-induced replication (BIR), which involves extensive and mutagenic DNA synthesis spanning up to hundreds of kilobases. It remains unknown how mutagenic BIR is suppressed at two-ended DSBs. Here, we demonstrate that BIR is suppressed at two-ended DSBs by proteins coordinating the usage of two ends of a DSB: (i) ssDNA annealing proteins Rad52 and Rad59 that promote second end capture, (ii) D-loop unwinding helicase Mph1, and (iii) Mre11-Rad50-Xrs2 complex that promotes synchronous resection of two ends of a DSB. Finally, BIR is also suppressed when Sir2 silences a normally heterochromatic repair template. All of these proteins are particularly important for limiting BIR when recombination occurs between short repetitive sequences, emphasizing the significance of these mechanisms for species carrying many repetitive elements such as humans.
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http://dx.doi.org/10.15252/embj.2020104847DOI Listing
April 2021

[Value of autism screening checklists in the early identification of autism spectrum disorder].

Zhongguo Dang Dai Er Ke Za Zhi 2021 Apr;23(4):343-349

Department of Health Care, Children's Hospital of Chongqing Medical University/Ministry of Education Key Laboratory of Child Development and Disorders/National Clinical Research Center for Child Health and Disorders/China International Science and Technology Cooperation Base of Child Development and Critical Disorders/Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.

Objective: To evaluate the value of autism screening checklists in the early identification of autism spectrum disorder (ASD).

Methods: A total of 2 571 children who attended the Children's Hospital of Chongqing Medical University and completed autism screening and diagnostic test were enrolled as subjects, among whom 2 074 were diagnosed with ASD, 261 were diagnosed with global developmental delay (GDD), 206 were diagnosed with developmental language disorder (DLD), and 30 had normal development. The sensitivity, specificity, and optimal threshold value of the Modified Checklist for Autism in Toddlers (M-CHAT) and the Autism Behavior Checklist (ABC) for the early identification of ASD were evaluated by the receiver operating characteristic (ROC) curve.

Results: The M-CHAT had a high sensitivity of 88.3% but a low specificity of 36.0% for the identification of ASD. Its sensitivity decreased with age, and was maintained above 80% for children aged 16 to < 48 months. The ABC had a high specificity of 87.3% but a low sensitivity of 27.2%, with an optimal cut-off value of 47.5 based on the ROC curve analysis. The multivariate linear regression model based on a combination of the M-CHAT and ABC for screening of ASD showed a specificity of 85.8% and a sensitivity of 56.6%.

Conclusions: The M-CHAT has a high sensitivity and a low specificity in the identification of ASD, with a better effect in children aged 16 to < 48 months. The ABC has a high specificity and a low sensitivity. The multiple linear regression model method based on the combined M-CHAT and ABC to screen ASD appears to be effective.
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April 2021

Nr4a1 promotes cell adhesion and fusion by regulating Zeb1 transcript levels in myoblasts.

Biochem Biophys Res Commun 2021 Apr 8;556:127-133. Epub 2021 Apr 8.

Department of Gerontology, ShengJing Hospital of China Medical University, Shenyang, Liaoning, 110004, China. Electronic address:

Nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as a myogenic factor in muscle development and regeneration; however, it remains unclear how Nr4a1 regulates myoblast physiology. In this study, report a role for Nr4a1-mediated regulation of cell adhesion in myoblast and muscle tissue. Nr4a1-overexpression myoblast, Nr4a1-konckdown myoblast and mice gastrocnemius muscle following an injection with an adenovirus vector expression Nr4a1 (Nr4a1-AAV) were used to observe the changes in cell adhesion. Nr4a1 was found to enhance cell-cell contact and adhesion molecule expression in myoblasts. In contrast, the deletion of Nr4a1 expression inhibited junction and adhesion between myoblasts. Moreover, Nr4a1 increased myoblast adhesion via directly binding to an upstream site of zinc finger E-box binding homeobox 1 (Zeb1), which is required for myogenesis in myoblasts. In mice, Zeb1 induced increased cadherin and integrin expression in the gastrocnemius muscle following an injection with an adenovirus vector expressing Nr4a1(Nr4a1-AAV). These data indicate that Nr4a1 regulates myoblast adhesion via Zeb1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.153DOI Listing
April 2021

Hydrogen-saturated saline mediated neuroprotection through autophagy via PI3K/AKT/mTOR pathway in early and medium stages of rotenone-induced Parkinson's disease rats.

Brain Res Bull 2021 Apr 7. Epub 2021 Apr 7.

Life science research center, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, China. Electronic address:

Some cardiovascular symptoms in the early stage of Parkinson's disease (PD) were related to degeneration of the rostral ventrolateral medulla (RVLM) catecholaminergic neurons. To date, little is known about the effects of hydrogen water on early stage of PD. Here, protective actions of hydrogen-saturated saline (HS) on rotenone-induced PD rats, as well as its underlying mechanisms were investigated. HS was used to treat PD rats at three general stages; early, medium and late, which were represented by rotenone induced rats for 0, 7 and 14 days. HS treatment significantly alleviated the cardiovascular and motor symptoms in rotenone-induced PD rats, improved the survival number of RVLM catecholaminergic neurons and nigral dopamine neurons only in early and medium stages of PD rats. Decreased levels of reactive oxygen species (ROS) and alpha-synuclein (α-Syn), transformation of microtubule associated protein 1 light chain 3 (LC3)-I/II and degradation of sequestosome 1 (p62) were detected, as well as increased expression level of autophagy related protein 5 (ATG5) and B-cell lymphoma-2 interacting protein 1 (Beclin-1) in the RVLM and substantia nigra (SN) after HS treatment in early and medium stages of PD rats. In addition, phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and mammalian rapamycin target protein (mTOR) decreased after HS treatment in early and medium stages of PD rats. The results suggested that HS treatment exerted beneficial effects in early and medium stages before motor impairments emerged but not in the late stage of rotenone-induced PD rats. It exerted neuroprotection with RVLM catecholaminergic neurons and nigral dopamine neurons, mediated in part by decreasing levels of ROS and α-Syn through increasing autophagy machinery which were partly via inhibiting PI3K-Akt-mTOR pathway.
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http://dx.doi.org/10.1016/j.brainresbull.2021.04.003DOI Listing
April 2021

Iso-anchorene is an endogenous metabolite that inhibits primary root growth in Arabidopsis.

Plant J 2021 Apr 10. Epub 2021 Apr 10.

King Abdullah University of Science and Technology (KAUST), Biological and Environmental Sciences and Engineering Division, Center for Desert Agriculture, The BioActives Lab, Thuwal, 23955-6900, Saudi Arabia.

Carotenoid-derived regulatory metabolites and hormones are generally known to arise through the oxidative cleavage of a single double bond in the carotenoid backbone, which yields mono-carbonyl products called apocarotenoids. However, the extended conjugated double bond system of these pigments predestines them also to repeated cleavage forming di-aldehyde products, diapocarotenoids, which have been less investigated due to their instability and low abundance. Recently, we reported on the short diapocarotenoid anchorene as an endogenous Arabidopsis metabolite and specific signaling molecule that promotes anchor root formation. In this work, we investigated the biological activity of a synthetic isomer of anchorene, iso-anchorene, which can derive from repeated carotenoid cleavage. We show that iso-anchorene is a growth inhibitor that specifically inhibits primary root growth by reducing cell division rates in the root apical meristem. Using auxin efflux transporter marker lines, we also show that the effect of iso-anchorene on primary root growth involves the modulation of auxin homeostasis. Moreover, by using liquid chromatography mass spectrometry (LC-MS) analysis, we demonstrate that iso-anchorene is a natural Arabidopsis metabolite. Chemical inhibition of carotenoid biosynthesis led to a significant decrease in the iso-anchorene level, indicating that it originates from this metabolic pathway. Taken together, our results reveal a further carotenoid-derived regulatory metabolite with a specific biological function that affects root growth, manifesting the biological importance of diapocarotenoids.
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http://dx.doi.org/10.1111/tpj.15271DOI Listing
April 2021

Clinical Application of Chromosomal Microarray Analysis in Pregnant Women with Advanced Maternal Age and Fetuses with Ultrasonographic Soft Markers.

Med Sci Monit 2021 Apr 10;27:e929074. Epub 2021 Apr 10.

Center of Reproductive Medicine and Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, Jilin, China (mainland).

BACKGROUND In pregnant women with advanced maternal age (AMA) and fetuses with ultrasonographic (USG) soft markers it is always challenging to decide whether to implement chromosomal microarray analysis (CMA) or not. It is unclear whether CMA should be used in the fetuses with isolated USG soft markers, and there is still a lack of extensive sample research. MATERIAL AND METHODS We enrolled 1521 cases in our research and divided them into 3 groups as follows: pregnant women with isolated AMA (group 1, n=633), pregnant women whose fetuses had isolated USG soft markers (group 2, n=750), and pregnant women with AMA whose fetuses had isolated USG soft markers (group 3, n=138). All pregnant women underwent prenatal ultrasound and amniocentesis, and fetal cells in the amniotic fluid were used for genetic analysis of CMA. All participants signed a written informed consent prior to CMA. RESULTS Abnormal findings were detected by CMA in 330 (21.70%) fetuses, including 37 (2.43%) clinically significant copy number variations (CNVs), 52 (3.42%) benign or likely benign CNVs, and 240 (15.78%) variants of unknown significance. The frequency of clinically significant CNVs in group 1 and group 2 were significantly lower than that in group 3 (2.37% and 2.0% vs 5.07%, P<0.01). More than a half (59.46%, 22/37) of the pregnant women decided to continue their pregnancy despite having a fetus diagnosed with clinically significant CNV. CONCLUSIONS CMA can increase the diagnostic yield of fetal chromosomal abnormality for pregnant women with isolated AMA or/and their fetuses had isolated USG soft markers.
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http://dx.doi.org/10.12659/MSM.929074DOI Listing
April 2021

[Application of goal-oriented fluid replacement therapy in volume management of postpartum hemorrhage during cesarean section].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021 Mar;33(3):305-310

Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.

Objective: To observe the effect of fluid therapy on volume and coagulation function in patients with severe postpartum hemorrhage during cesarean section of placenta accreta under the guidance of inferior vena cava diameter (IVCD) and inferior vena cava collapse index (IVC-CI).

Methods: A prospective randomized controlled study was conducted in 60 pregnant women with severe postpartum hemorrhage (blood loss ≥ 1 000 mL) who were hospitalized for delivery or referred for delivery in the Peking University Third Hospital from December 2018 to July 2019. The patients were divided into routine fluid replacement group and goal-oriented fluid resuscitation group (goal-oriented fluid replacement therapy was given) according to the different ways of fluid replacement. The hemodynamics, blood gas analysis, coagulation function, total fluid replacement, urine volume, prognosis, intraoperative vasoactive drugs utilization rate and postoperative adverse events were recorded before skin incision, after the fetus delivered, postpartum hemorrhage and at the end of operation, and the differences of these indices between the two groups were compared.

Results: (1) Hemodynamics: the heart rate (HR) of the two groups were reached the peak during postpartum hemorrhage, but there was no significant difference in HR at each time point between the two groups. The mean arterial pressure (MAP) was decreased at first and then increased in both groups, and reached the trough at postpartum hemorrhage, but the MAP in the goal-oriented fluid resuscitation group was significantly higher than that in the routine fluid replacement group [mmHg (1 mmHg = 0.133 kPa): 75.6±10.7 vs. 69.2±8.9, P < 0.05]. In the goal-oriented fluid resuscitation group, the central venous pressure (CVP) was increased slightly after the fetus delivered and then stabilized, while in the routine fluid replacement group, the CVP was increased at first and then decreased, and reached the peak in postpartum hemorrhage. During postpartum hemorrhage, CVP in the goal-oriented fluid resuscitation group was significantly lower than that in the routine fluid replacement group [cmHO (1 cmHO = 0.098 kPa): 9.5±3.9 vs. 11.4±3.4, P < 0.05]. (2) Arterial blood gas: partial pressure of oxygen (PaO) and partial pressure of carbon dioxide (PaCO) in arterial blood at the end of operation in both groups were higher than those in postpartum hemorrhage. There was no significant difference in PaO at the end of operation between the goal-oriented fluid resuscitation group and routine fluid replacement group (mmHg: 189.3±100.5 vs. 240.2±126.3, P > 0.05). The PaCO in the goal-oriented fluid resuscitation group was significantly lower than that in the routine fluid replacement group (mmHg: 34.6±4.6 vs. 36.8±4.1, P < 0.05). The lactic acid (Lac) at the end of operation of the goal-oriented fluid resuscitation group was significantly lower than that of the routine fluid replacement group (mmol/L: 2.2±0.6 vs. 2.6±1.1, P < 0.05). (3) Liquid intake and output volume: the total infusion volume, crystal fluid infusion volume and suspended red blood cell infusion volume in the goal-oriented fluid resuscitation group were significantly less than those in the routine fluid replacement group [total infusion volume (mL): 3 385.9±1 144.1 vs. 4 448.3±1 194.4, crystal infusion volume (mL): 2 635.6±789.7 vs. 3 160.0±860.3, suspended red blood cell input volume (mL): 695.6±366.2 vs. 911.1±284.7, all P < 0.05], and the utilization rate of vasoactive drugs in the goal-oriented fluid resuscitation group was decreased significantly during operation [13.3% (4/30) vs. 60.0% (18/30), P < 0.05]. The amount of bleeding in the goal-oriented fluid resuscitation group was also significantly less than that in the routine fluid replacement group (mL: 1 451.7±373.8 vs. 1 725.9±372.8, P < 0.05), but there was no significant difference in urine volume between the goal-oriented fluid resuscitation group and the routine fluid replacement group (mL: 369.0±262.7 vs. 485.0±286.8, P > 0.05). (4) Coagulation function: at the end of operation, the prothrombin time (PT) in the goal-oriented fluid resuscitation group was significantly shorter than that in the routine fluid replacement group (s: 10.9±0.6 vs. 11.2±0.6), and the fibrinogen (Fib) in the goal-oriented fluid resuscitation group was significantly higher than that in the routine fluid replacement group (g/L: 3.7±0.5 vs. 2.9±0.8), and the differences were statistically significant (both P < 0.05). (5) Prognostic index: compared with the routine fluid replacement group, the proportion of patients transferred to intensive care unit (ICU) at the end of operation in the goal-oriented fluid resuscitation group was significantly lower [16.7% (5/30) vs. 66.7% (20/30), P < 0.05], and ICU length-of-stay was significantly shorter [hours: 0 (0, 24) vs. 24 (0, 24), P < 0.05], but there was no significant difference in the incidence of disseminated intravascular coagulation (DIC), acute renal injury (AKI) or hysterectomy between the goal-oriented fluid resuscitation group and the routine fluid replacement group [the incidence of DIC: 0% (0/30) vs. 6.7% (2/30), the incidence of AKI: 0% (0/30) vs. 3.3% (1/30), the hysterectomy rate: 10.0% (3/30) vs. 26.7% (8/30), all P > 0.05].

Conclusions: Fluid resuscitation guided by IVC-CI can effectively reduce the volume of blood and fluid transfusion and blood loss in patients with severe postpartum hemorrhage and improve their blood coagulation function.
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http://dx.doi.org/10.3760/cma.j.cn121430-20201016-00672DOI Listing
March 2021

Small dome-shaped pigment epithelium detachment in polypoidal choroidal vasculopathy: an under-recognized sign of polypoidal lesions on optical coherence tomography?

Eye (Lond) 2021 Apr 8. Epub 2021 Apr 8.

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Purpose: To evaluate the diagnostic accuracy of spectral-domain optical coherence tomography (SD-OCT) and swept-source optical coherence tomographic angiography (SS-OCTA) to identify polypoidal lesions in serous or serosanguinous maculopathy.

Materials And Methods: A retrospective review of patients presenting pigment epithelial detachments (PEDs) with the diagnosis of polypoidal choroidal vasculopathy (PCV), neovascular age-related macular degeneration (nAMD), and central serous chorioretinopathy (CSC), all of which underwent SD-OCT, SS-OCTA, and indocyanine green angiography (ICGA). Typical features of polypoidal lesions on SD-OCT included sharply peaked PED, notched PED, and hyperreflective ring underneath PED. SS-OCTA feature was vascularized PEDs on cross-sectional images corresponding to cluster-like structures on en face images. The parameters of PEDs were measured for analysis.

Results: Of 72 eyes, 30 had PCV, 22 had nAMD, and 20 had CSC. A total of 128 localized PEDs were detected on SD-OCT. Typical features on SD-OCT had a high specificity (94.0%) but a limited sensitivity (73.8%). SS-OCTA features provided a higher sensitivity (96.7%). PEDs of the polypoidal lesions unrecognized by SD-OCT were dome-shaped, with smaller ratio of height to base diameter and less area, and almost had heterogeneous internal reflectivity and a connected double-layer sign. Some lesions misidentified by SS-OCTA developed into ICGA-proven polypoidal lesions at follow-up visits.

Conclusion: A small dome-shaped PED with heterogeneous internal reflectivity and a connected double-layer sign on SD-OCT may suggest a polypoidal lesion of PCV. SS-OCTA may be a helpful tool to investigate preclinical PCV and observe the formation of polypoidal lesions.
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http://dx.doi.org/10.1038/s41433-020-01390-0DOI Listing
April 2021

A novel 125I seeds fixed on gastric tube for treatment of inoperable esophageal carcinoma: A case report.

Medicine (Baltimore) 2021 Apr;100(14):e25410

Department of Cardiothoracic Surgery, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China.

Abstract: To explore the treatment benefit of 125I seeds fixed on a gastric tube in the early inoperable esophageal carcinoma (EC).Three senile patients with early inoperable EC who were treated with brachytherapy between October 2017 and February 2019 were included in this study. 125I seeds were fixed on the gastric tube, which was then inserted on the surface of the EC. One patient suffered from severe pulmonary insufficiency; 1 patient underwent colon cancer surgery one week before treatment and suffered from liver dysfunction and esophageal varices; 1 patient suffered from venous embolism of lower extremities and pulmonary artery embolism.All three patients were successfully operated and completed treatment. During the operation, no displacement and shedding of 125I seed gastric tube occurred. After surgery, the discomfort while swallowing and pain after eating were significantly improved. Moreover, dysphagia was relieved in patient 3. In addition, no complications, such as perforation or bleeding, occurred. Local lesions were effectively controlled.Gastric tube with 125I seeds provides a new treatment protocol for inoperable EC and malignant obstruction of esophageal carcinoma.
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http://dx.doi.org/10.1097/MD.0000000000025410DOI Listing
April 2021

Apolipoprotein M promotes cholesterol uptake and efflux from mouse macrophages.

FEBS Open Bio 2021 Apr 8. Epub 2021 Apr 8.

Clinical Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.

Apolipoprotein M (ApoM) exhibits various anti-atherosclerotic functions as a component of high-density lipoprotein (HDL) particles. Scavenger receptor class B type I (SR-BI) is a classic HDL receptor that mediates selective cholesterol uptake and enhances the efflux of cellular cholesterol to HDL. However, the effect of ApoM on cholesterol transport in macrophages remains unclear. In this study, we identified for the first time that ApoM is expressed in mouse macrophages and is involved in cholesterol uptake, similar to SR-BI. NBD-cholesterol uptake and efflux in cells were characterized using fluorescence spectrophotometry. The uptake ratios of cholesterol by macrophages from ApoM SR-BI mice were significantly lower than those from ApoM SR-BI and ApoM SR-BI mice. Real-time fluorescence quantitative PCR was used to analyze the expression of cholesterol transport-related genes involved in cholesterol uptake. ApoM-enriched HDL (ApoM HDL) facilitated more cholesterol efflux from murine macrophage Ana-1 cells than ApoM-free HDL (ApoM HDL). However, recombinant human ApoM protein inhibited the ability of ApoM HDL to induce cholesterol efflux. In conclusion, ApoM promotes cholesterol uptake and efflux in mouse macrophages. A better understanding of ApoM function may lead to the development of novel therapeutic strategies for treating atherosclerotic diseases.
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http://dx.doi.org/10.1002/2211-5463.13157DOI Listing
April 2021

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study.

Oncologist 2021 Apr 8. Epub 2021 Apr 8.

Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.

Lessons Learned: Bevacizumab combined with S-1 and raltitrexed demonstrated positive anti-tumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer.

Background: In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed.

Methods: This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion, were eligible for this trial. Anti-EGFR therapy (for tumors with wild-type RAS) and anti-VEGF in first- or second-line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m on day 1), every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.

Results: From Sep 2015 to Nov 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated.

Conclusion: Bevacizumab combined with S-1 and raltitrexed showed promising anti-tumor activity and safety in refractory mCRC.
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http://dx.doi.org/10.1002/onco.13778DOI Listing
April 2021

Straw mulching and nitrogen application altered ammonia oxidizers communities and improved soil quality in the alkaline purple soil of southwest China.

AMB Express 2021 Apr 7;11(1):52. Epub 2021 Apr 7.

Soil and Fertilizer Institute, Sichuan Academy of Agricultural Sciences, Chengdu, 610066, Sichuan Province, China.

Microbe-mediated ammonia oxidation is a key process in soil nitrogen cycle. However, the effect of maize straw mulching on the ammonia oxidizers in the alkaline purple soil remains largely unknown. A three-year positioning experiment was designed as follows: straw mulching measures as the main-plot treatment and three kinds of nitrogen application as the sub-plot treatment. We found the contents of soil organic carbon (SOC), total nitrogen (TN), available potassium (AK), available nitrogen (AN), available phosphorus (AP), and NH-N were increased after straw mulching and nitrogen application in alkaline purple soil, so did the amoA genes abundance of ammonia-oxidizing archaeal (AOA) and bacterial (AOB). Terminal restriction fragment length polymorphism (T-RFLP) analysis revealed that Thaumarchaeote (448-bp T-RF) was dominated the AOA communities, whereas Nitrosospira sp (111-bp T-RF) dominated the AOB communities. The community compositions of both AOA and AOB were altered by straw mulching and nitrogen application in alkaline purple soil, however, the AOB communities was more responsive than AOA communities to the straw mulching and nitrogen application. Further analysis indicated that SOC and AP were the main factors affecting the abundance and community compositions of AOA and AOB in alkaline purple soil. The present study reported that straw mulching and nitrogen strategies differently shape the soil ammonia oxidizers community structure and abundance, which should be considered when evaluating agricultural management strategies regarding their sustainability and soil quality.
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http://dx.doi.org/10.1186/s13568-021-01211-xDOI Listing
April 2021

Localized ALK-positive histiocytosis in a Chinese woman: report of a case in the lung with a novel EML4-ALK rearrangement.

Virchows Arch 2021 Apr 7. Epub 2021 Apr 7.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.

ALK-positive histiocytosis (APH) is a newly defined entity with specific histological features and a highly recurrent KIF5B-ALK gene fusion. APH is characterized by clonal proliferation of histiocytes and can present as either systemic or localized. It was first described in infants and then expanded to older children and adults. Although lung involvement has been shown in three systemic cases, localized lung lesions have not previously been reported. The ALK gene has many fusion partners in addition to KIF5B in APH. Here, we report a striking case of localized APH in the lung harboring a rare EML4-ALK rearrangement in a 52-year-old Chinese woman. Furthermore, we reviewed the previously published APH cases, analyzed the partner genes of the ALK fusions, and explored the role of patient ethnicity. We discovered a link between ethnicity and this rare disease.
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http://dx.doi.org/10.1007/s00428-021-03092-8DOI Listing
April 2021

Recent Developed Strategies for Enhancing Chondrogenic Differentiation of MSC: Impact on MSC-Based Therapy for Cartilage Regeneration.

Stem Cells Int 2021 20;2021:8830834. Epub 2021 Mar 20.

Institute of Orthopaedics, Chinese PLA General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, 28 Fuxing Road, Haidian District, Beijing, China.

Articular cartilage is susceptible to damage, but its self-repair is hindered by its avascular nature. Traditional treatment methods are not able to achieve satisfactory repair effects, and the development of tissue engineering techniques has shed new light on cartilage regeneration. Mesenchymal stem cells (MSCs) are one of the most commonly used seed cells in cartilage tissue engineering. However, MSCs tend to lose their multipotency, and the composition and structure of cartilage-like tissues formed by MSCs are far from those of native cartilage. Thus, there is an urgent need to develop strategies that promote MSC chondrogenic differentiation to give rise to durable and phenotypically correct regenerated cartilage. This review provides an overview of recent advances in enhancement strategies for MSC chondrogenic differentiation, including optimization of bioactive factors, culture conditions, cell type selection, coculture, gene editing, scaffolds, and physical stimulation. This review will aid the further understanding of the MSC chondrogenic differentiation process and enable improvement of MSC-based cartilage tissue engineering.
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http://dx.doi.org/10.1155/2021/8830834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007380PMC
March 2021

Effect of SGLT-2 inhibitors on cardiovascular outcomes in heart failure patients: A meta-analysis of randomized controlled trials.

Eur J Intern Med 2021 Apr 3. Epub 2021 Apr 3.

Department of Endocrinology, Xuzhou Medical College Affiliated Hospital, Xuzhou, 221006, China. Electronic address:

Background: To investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus.

Methods: Electronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM).

Results: A total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72-0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62-0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76-0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77-0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86-0.93).

Conclusions: Compared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF.
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http://dx.doi.org/10.1016/j.ejim.2021.03.020DOI Listing
April 2021

Survival Following Edge-to-Edge Transcatheter Mitral Valve Repair in Patients With Cardiogenic Shock: A Nationwide Analysis.

J Am Heart Assoc 2021 Apr 6:e019882. Epub 2021 Apr 6.

Inova Heart and Vascular Institute Falls Church VA.

Background Edge-to-edge transcatheter mitral valve repair as salvage therapy in high surgical risk patients with severe mitral regurgitation presenting with cardiogenic shock (CS) has been described in small case series, but large clinical results have not been reported. This study aimed to evaluate outcomes of transcatheter mitral valve repair with MitraClip in patients with mitral regurgitation and CS using a large national database. Methods and Results From January 2014 to March 2019, we identified hospitalizations for CS in patients with mitral valve disease using data from Centers for Medicare and Medicaid Services. Those with a prior surgical or percutaneous mitral valve intervention were excluded. We compared survival between patients who underwent MitraClip during the index hospitalization and those who did not using propensity-matched analysis. The analysis included 38 166 patients (mean age, 71±11 years, 41.6% women) of whom 622 (1.6%) underwent MitraClip. MitraClip was increasingly used during CS hospitalizations over the study period (<0.001). After matching, patients receiving MitraClip had significantly lower in-hospital mortality (odds ratio, 0.6; 95% CI, 0.47-0.77; <0.001) and 1-year mortality (hazard ratio, 0.76; 95% CI, 0.65-0.88; <0.001) compared with those without MitraClip. The survival benefit associated with MitraClip was consistent across subgroups of interest, with the exception of patients requiring acute mechanical circulatory support or hemodialysis at index. Conclusions In patients with mitral regurgitation presenting with CS, use of MitraClip is increasing and associated with greater in-hospital and 1-year survival. Further studies are warranted to optimize patient selection and procedure timing for those receiving MitraClip as a treatment option in CS.
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http://dx.doi.org/10.1161/JAHA.120.019882DOI Listing
April 2021

Microbiome assembly for sulfonamide subsistence and the transfer of genetic determinants.

ISME J 2021 Apr 5. Epub 2021 Apr 5.

Environmental Microbiome Engineering and Biotechnology Lab, Department of Civil Engineering, The University of Hong Kong, Hong Kong, China.

Antibiotic subsistence in bacteria represents an alternative resistance machinery, while paradoxically, it is also a cure for environmental resistance. Antibiotic-subsisting bacteria can detoxify antibiotic-polluted environments and prevent the development of antibiotic resistance in environments. However, progress toward efficient in situ engineering of antibiotic-subsisting bacteria is hindered by the lack of mechanistic and predictive understanding of the assembly of the functioning microbiome. By top-down manipulation of wastewater microbiomes using sulfadiazine as the single limiting source, we monitored the ecological selection process that forces the wastewater microbiome to perform efficient sulfadiazine subsistence. We found that the community-level assembly selects for the same three families rising to prominence across different initial pools of microbiomes. We further analyzed the assembly patterns using a linear model. Detailed inspections of the sulfonamide metabolic gene clusters in individual genomes of isolates and assembled metagenomes reveal limited transfer potential beyond the boundaries of the Micrococcaceae lineage. Our results open up new possibilities for engineering specialist bacteria for environmental applications.
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http://dx.doi.org/10.1038/s41396-021-00969-zDOI Listing
April 2021

Brain circuit dysfunction in specific symptoms of depression.

Eur J Neurosci 2021 Apr 5. Epub 2021 Apr 5.

New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.

Since the depressive disorder manifests complex and diverse symptoms clinically, its pathological mechanism and therapeutic options are difficult to determine. In recent years, the advent of optogenetics, chemogenetics and viral tracing techniques, along with the well-established rodent model of depression, has led to a shift in the focus of depression research from single molecules to neural circuits. In virtue of the powerful tools above, psychiatric disorder such as depression could be well related to the disfunction of brain's connection. Moreover, compelling studies also support that the diversity of depressive behaviour could be involved with the discrete changes in a distinct circuit of the brain. Therefore, summarising the differential changes of the neural circuits in mice with depression-like behaviour may provide a better understanding of the causal relationships between neural circuit and depressive behaviour. Here, we focus on the changes in the neural circuitry underlying various depression-like phenotypes, including motivation, despair, social avoidance and comorbid sequelae, which may provide an explanation to circuit-specific discrepancy in depression-like behaviour.
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http://dx.doi.org/10.1111/ejn.15221DOI Listing
April 2021

Gains or losses? A quantitative estimation of environmental and economic effects of an ecological compensation policy.

Ecol Appl 2021 Apr 4:e2341. Epub 2021 Apr 4.

School of Economics and Management, China University of Geosciences, Beijing, 100083, China.

Ecological compensation is an innovative and effective tool to explore the coordinated development of socioeconomic prosperity and ecological protection, especially for a watershed crossing different regions. It converts the externalities of ecosystem services into practical financial incentives for local stakeholders. This empirical study applies a quantitative policy evaluation approach to evaluate the environmental and economic effects of an ecological compensation policy, using the paddy land-to-dry land (PLDL) program implemented in China's Miyun Reservoir watershed as an example. The study is based on responses to a 2017 questionnaire regarding agricultural production inputs and outputs administered to 269 households in Hebei Province, where the PLDL program has been operational for over ten years. The results show that the program has reduced nitrogen usage by 24% on average in 2017 and decreased the total nitrogen emission load by 16.98 tons for the entire case area, which accounts for approximately 18.6% of the total nitrogen load reduction of the Miyun Reservoir basin. However, the upstream households involved in this program have experienced agricultural income losses higher than that allowed for by the current compensation criterion. Therefore, this paper discusses the factors that should be considered in the process of determining ecological compensation criteria. In particular, the paper proposes a differential compensation scheme based on the environmental effect at the individual level to avoid a standard payment for all households irrespective of their different contributions. This differential compensation payment scheme facilitates the fair treatment of environmental contributors and maximizes environmental benefits through an equitable allocation of limited ecological compensation funds. This study serves as a theoretical and practical reference for further improvement of the current ecological compensation policy in China. The study also sheds light on practices for estimating ecological compensation criteria and formulating ecological compensation policies for other regions or countries in the future.
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http://dx.doi.org/10.1002/eap.2341DOI Listing
April 2021

YTHDF1 Aggravates the Progression of Cervical Cancer Through mA-Mediated Up-Regulation of RANBP2.

Front Oncol 2021 19;11:650383. Epub 2021 Mar 19.

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.

N6-methyladenosine (mA) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various cancers. YTHDF1 acts as a crucial mA "reader" and regulates the fate of mA modified mRNA. However, its role in cervical cancer remains unknown. In this study, we showed that YTHDF1 was highly expressed in cervical cancer, and was closely associated with the poor prognosis of cervical cancer patients. YTHDF1 knockdown suppressed the growth, migration and invasion, and induced apoptosis of cervical cancer cells. Moreover, YTHDF1 knockdown inhibited tumorigenesis of cervical cancer cells . Through combined on-line data analysis of RIP-seq, meRIP-seq and Ribo-seq upon YTHDF1 knockdown, RANBP2 was identified as the key target of YTHDF1 in cervical cancer cells. YTHDF1 regulated RANBP2 translation in an mA-dependent manner without effect on its mRNA expression. RANBP2 potentiated the growth, migration and invasion of cervical cancer cells. Our study demonstrated the oncogenic role of YTHDF1 in cervical cancer by regulating RANBP2 expression and YTHDF1 represents a potential target for cervical cancer therapy.
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http://dx.doi.org/10.3389/fonc.2021.650383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017305PMC
March 2021

Brain transcriptomics of nonhuman primates: a review.

Neurosci Lett 2021 Apr 1:135872. Epub 2021 Apr 1.

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Peking University Third Hospital, Beijing, 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, 100191, China. Electronic address:

The brain is one of the most important and intricate organs in our bodies. Interpreting brain function and illustrating the changes and molecular mechanisms during physiological or pathological processes are essential but sometimes difficult to achieve. In addition to histology, ethology and pharmacology, the development of transcriptomics alleviates this condition by enabling high-throughput observation of the brain at various levels of anatomical specificity. Moreover, because human brain samples are scarce, the brains of nonhuman primates are important alternative models. Here in this review, we summarize the applications of transcriptomics in nonhuman primate brain studies, including investigations of brain development, aging, toxic effects and diseases. Overall, as a powerful tool with developmental potential, transcriptomics has been widely utilized in neuroscience.
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http://dx.doi.org/10.1016/j.neulet.2021.135872DOI Listing
April 2021

Recognition of Hydrophilic Cyclic Compounds by a Water-Soluble Cavitand.

Molecules 2021 Mar 30;26(7). Epub 2021 Mar 30.

Center for Supramolecular Chemistry & Catalysis and Department of Chemistry, College of Science, Shanghai University, 99 Shang-Da Road, Shanghai 200444, China.

A water-soluble deep cavitand bearing amides on the upper rim and trimethyl ammonium groups on the feet was synthesized. The open-ended cavity is stabilized by the intramolecular hydrogen bonds formed between the adjacent amides, and the introduction of trimethylammonium imparts to the cavitand good solubility in water. The cavitand exhibits high binding affinity and selectivity to hydrophilic molecules in water. With certain guests, such as cyclohexyl alcohols, amines and acids, the recognition involves the synergistic action of hydrogen bonding with hydrophobic effects. The binding phenomena are interpreted in terms of a fixed solvent cage presented by the host to the guest.
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http://dx.doi.org/10.3390/molecules26071922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037811PMC
March 2021

Subcritical Water Extraction of .

Molecules 2021 Mar 15;26(6). Epub 2021 Mar 15.

Department of Chemistry, East Carolina University, Greenville, NC 27858, USA.

In this work, a green extraction technique, subcritical water extraction (SBWE), was employed to extract active pharmaceutical ingredients (APIs) from an important Chinese medicinal herb, (danshen), at various temperatures. The APIs included tanshinone I, tanshinone IIA, protocatechualdehyde, caffeic acid, and ferulic acid. Traditional herbal decoction (THD) of was also carried out for comparison purposes. Reproduction assay of herbal extracts obtained by both SBWE and THD were then conducted on so that SBWE conditions could be optimized for the purpose of developing efficacious herbal medicine from The extraction efficiency was mostly enhanced with increasing extraction temperature. The quantity of tanshinone I in the herbal extract obtained by SBWE at 150 °C was 370-fold higher than that achieved by THD extraction. Reproduction evaluation revealed that the worm reproduction rate decreased and the reproduction inhibition rate increased with elevated SBWE temperatures. Most importantly, the reproduction inhibition rate of the SBWE herbal extracts obtained at all four temperatures investigated was higher than that of traditional herbal decoction extracts. The results of this work show that there are several benefits of subcritical water extraction of medicinal herbs over other existing herbal medicine preparation techniques. Compared to THD, the thousand-year-old and yet still popular herbal preparation method used in herbal medicine, subcritical water extraction is conducted in a closed system where no loss of volatile active pharmaceutical ingredients occurs, although analyte degradation may happen at higher temperatures. Temperature optimization in SBWE makes it possible to be more efficient in extracting APIs from medicinal herbs than the THD method. Compared to other industrial processes of producing herbal medicine, subcritical water extraction eliminates toxic organic solvents. Thus, subcritical water extraction is not only environmentally friendly but also produces safer herbal medicine for patients.
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http://dx.doi.org/10.3390/molecules26061634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001979PMC
March 2021

Low-Dose Aspirin Prevents Kidney Damage in LPS-Induced Preeclampsia by Inhibiting the WNT5A and NF-κB Signaling Pathways.

Front Endocrinol (Lausanne) 2021 11;12:639592. Epub 2021 Mar 11.

Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.

Preeclampsia (PE) is a serious pregnancy-related disease, and patients usually present with a high inflammatory response. Previous studies have suggested that aspirin (ASP) may have a role in alleviating the pathogenesis of preeclampsia. However, whether ASP can improve kidney damage and the mechanism for improving it is currently unclear. Here we optimized a lipopolysaccharide (LPS)-induced PE mouse model to identify the role of ASP in renal protection. We found that ASP treatment ameliorated LPS-induced renal failure and pathological changes, the tubular injury was significantly attenuated by ASP. Administration of ASP decreased the renal expression of pro-inflammatory factors, resulting in reduced kidney inflammation. The number of GALECTIN-3-positive cells was reduced, and the up-regulation of IL-6 and TNF-α was decreased. In addition, ASP also suppressed renal cell apoptosis and oxidative stress. An study indicated that ASP relieved LPS-induced HK-2 cell damage by inhibiting WNT5A/NF-κB signaling. Collectively, our data suggest that ASP is a useful therapeutic option for PE-related kidney injury.
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http://dx.doi.org/10.3389/fendo.2021.639592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006287PMC
March 2021

[Research on chemical constituents from Artemisia annua Ⅰ].

Zhongguo Zhong Yao Za Zhi 2021 Mar;46(5):1160-1167

Institute of Traditional Chinese Medicine and Natural Products,College of Pharmacy,Jinan University Guangzhou 510632,China.

Chemical constituents were isolated and purified from the water extract of Artemisia annua by column chromatography of HP-20 macroporous resin, silica gel, ODS, Sephadex LH-20, HW-40, and semi-preparative RP-HPLC. Their structures were elucidated by physicochemical properties and spectral analyses. As a result, Fifteen compounds were isolated and identified as vitexnegheteroin M(1), sibricose A5(2), securoside A(3), citrusin D(4), annphenone(5), E-melilotoside(6), esculetin(7), scopoletin-7-O-β-D-glucoside(8), eleutheroside B_1(9), chrysosplenol D(10), patuletin-3-O-β-D-glucopyranoside(11), quercetin-7-O-β-D-glucoside(12), rutin(13), apigenin 6,8-di-C-β-D-glucopyranoside(14), isoschaftoside(15), among them, compounds 1-4 were identified from Artemisia for the first time. Additionally, the isolates were evaluated for their inhibitory effects on the production of PGE_2 in LPS-simulated RAW264.7 macrophages. The results showed that compounds 1, 2, 8, and 10-15 could reduce PGE_2 levels, to a certain extent.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210107.601DOI Listing
March 2021

Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects.

Gut 2021 Mar 30. Epub 2021 Mar 30.

Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queens University, Kingston, Ontario, Canada.

Objective: The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues.

Design: Antinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells.

Results: NFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis.

Conclusion: In a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.
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http://dx.doi.org/10.1136/gutjnl-2021-324070DOI Listing
March 2021