Publications by authors named "Chu Chu"

105 Publications

A novel high-resolution monophenolase/diphenolase/radical scavenging profiling for the rapid screening of natural whitening candidates from Peaonia lactiflora root and their mechanism study with molecular docking.

J Ethnopharmacol 2021 Sep 7:114607. Epub 2021 Sep 7.

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China. Electronic address:

Ethnopharmacological Relevance: The root of Paeonia lactiflora is a traditionally-used whitening medicine in China for thousands of years. Although some tyrosinase inhibitors and/or antioxidants such as 1,2,3,4,6-pentagalloylglucose, gallic acid, have been isolated and identified, their tyrosinase inhibition pathway (monophenolase or diphenolase inhibition, or both two) have not been systematically studied and the underlying tyrosinase inhibition mechanism has not been revealed yet. Moreover, the exploring of new natural tyrosinase inhibitors and antioxidants is urgently needed.

Aim Of The Study: This review aimed to develop a new microplate-based high-resolution tyrosinase inhibition profiling assay and establish a furthermore triple high-resolution monophenolase/diphenolase/radical scavenging profiling for accelerating identification bioactive compounds from complicated plant extract.

Materials And Methods: The targeted isolation and structure elucidation were performed with high-performance liquid chromatography-high-resolution mass spectrometry and preparative high-performance liquid chromatography. It allows to be a proof of concept with the root of Paeonia lactiflora crude extract as a natural whitening herbal drug.

Results: The result showed that galloylpaeoniflorin specifically inhibited monophenolase activity. While 1,2,3,4,6-pentagalloylglucose, gallic acid and catechin demonstrated the inhibition towards both monophenolase and diphenolase. Among them, 1,2,3,4,6-pentagalloylglucose can inhibit monophenolase activity was reported for the first time. In addition, antioxidant properties were attributed to catechin, 1,2,3,4,6-pentagalloylglucose and gallic acid. Due to its low content and complicated configuration in the root of Paeonia lactiflora, a new potential tyrosinase inhibitor and radical scavenger which tentatively identified as hexagalloylglucose by high-resolution MS was still need further verification. What's more, the molecular docking unveiled that bioactive enzymatic inhibitors mainly interacted with amino acid catalytic residues of tyrosinase via H-bonds and van der wals, which may be helpful to understand their inhibition mechanisms with tyrosinase in the skin whitening.

Conclusions: The platform provided a promising and efficient strategy for the rapid screening of whitening active components from natural sources.
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http://dx.doi.org/10.1016/j.jep.2021.114607DOI Listing
September 2021

Amnion signals are essential for mesoderm formation in primates.

Nat Commun 2021 08 26;12(1):5126. Epub 2021 Aug 26.

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Embryonic development is largely conserved among mammals. However, certain genes show divergent functions. By generating a transcriptional atlas containing >30,000 cells from post-implantation non-human primate embryos, we uncover that ISL1, a gene with a well-established role in cardiogenesis, controls a gene regulatory network in primate amnion. CRISPR/Cas9-targeting of ISL1 results in non-human primate embryos which do not yield viable offspring, demonstrating that ISL1 is critically required in primate embryogenesis. On a cellular level, mutant ISL1 embryos display a failure in mesoderm formation due to reduced BMP4 signaling from the amnion. Via loss of function and rescue studies in human embryonic stem cells we confirm a similar role of ISL1 in human in vitro derived amnion. This study highlights the importance of the amnion as a signaling center during primate mesoderm formation and demonstrates the potential of in vitro primate model systems to dissect the genetics of early human embryonic development.
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http://dx.doi.org/10.1038/s41467-021-25186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390679PMC
August 2021

HPLC fingerprinting-based multivariate analysis of chemical components in Tetrastigma Hemsleyanum Diels et Gilg: Correlation to their antioxidant and neuraminidase inhibition activities.

J Pharm Biomed Anal 2021 Aug 8;205:114314. Epub 2021 Aug 8.

College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address:

Tetrastigma Hemsleyanum Diels & Gilg (TDG) has attracted growing attention in China; however, there were few studies on its bioactive components. Herein, the characteristic chemical components and dual antioxidant and neuraminidase inhibitory activities of fifteen batches of TDG from different places of origin and their relevance were investigated. The HPLC fingerprint was first established and the marker components were identified by using UPLC-Q-TOF-MS/MS. Catechin-5-O-β-d-glucopyranoside, tartaric acid, (1R, 2R, 4S)-2-hydroxy-1, 8-cineole-β-d-glucopyranoside, and phlorizin were identified for the first time. The result of multivariate statistical analysis indicated that multiple components have a significant contribution to the classification of TDG, such as chlorogenic acid, saccharumoside C/D, robinin, procyanidin B, rutin, isoquercitrin, etc. Then, the antioxidant and neuraminidase inhibitory activities of fifteen batches of TDG were measured. The result of grey relationship analysis showed that the contents of rutin, isoquercitrin, kaempferol-3-rutinoside, and astragalin were positively correlated with these two activities with correlation coefficients more than 0.8. The quantitative analysis of these four bioactive compounds was performed by using HPLC-DAD. The recovery rate of the method varied from 98.02% to 100.21%, the RSD values of precision, stability and repeatability were between 1.32-3.15 %, and the R value of the linear equation was above 0.9990. To sum up, this study is valuable in the quality control of TDG.
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http://dx.doi.org/10.1016/j.jpba.2021.114314DOI Listing
August 2021

TLR2 deficiency promotes IgE and inhibits IgG1 class-switching following ovalbumin sensitization.

Ital J Pediatr 2021 Jul 27;47(1):162. Epub 2021 Jul 27.

Children's Hospital of Soochow University, Suzhou, 215003, People's Republic of China.

Background: To explore the roles of Toll-like receptor (TLR)2 in Th2 cytokine production and immunoglobulin (Ig) class switching following ovalbumin (OVA) sensitization.

Methods: TLR2 and wild-type C57BL/6 mice were sensitized by intraperitoneal injection with OVA. Lung pathology was assessed by hematoxylin and eosin staining. Abundance of interleukin (IL)4, IL5, IL13, and IL21 transcripts in the lungs was quantified by RT-PCR. OVA-specific IgG1, IgG2a, IgG2b, IgE and IgM were quantified by enzyme-linked immunosorbent assay. Phosphorylated signal transducer and activator of transcription (STAT)3 in lung tissue was detected by immunohistochemistry staining and nuclear factor (NF) κB activation was measured by immunofluorescence staining. STAT3 activation was inhibited using cryptotanshinone (CPT) treatment. Germline transcripts (Iμ-Cμ, Iγ-Cγ, Iα-Cα or Iε-Cε), post-recombination transcripts (Iμ-Cγ, Iμ-Cα or Iμ- Cε) and mature transcripts (VDJ-Cγ, VDJ-Cα or VDJ-Cε) were analyzed from splenic B cells of OVA-sensitized wild-type mice (with or without CPT treatment) and TLR2 mice (with or without IL21 treatment).

Results: The lungs of TLR2 mice showed a lesser degree of inflammation than wild-type mice after OVA sensitization. Following OVA sensitization, levels of IL4, IL13, and IL21, but not IL5, were significantly lower in TLR2 compared with wild-type mice. Moreover, OVA-specific IgG1 and IgE titers were markedly lower and higher, respectively, in TLR2 mice. TLR2 deficiency inhibited STAT3 activation but not NF-κB p65 activation. CPT treatment reduced IgG1 titers via inhibition of Stat3 phosphorylation. Both TLR2 knockout and CPT treatment reduced the frequencies of Iγ1-Cγ1, Iγ3-Cγ3 and Iα-Cα transcripts, but IL21 treatment compensated for the effects of TLR2 deficiency.

Conclusion: These results suggest a role of TLR2 in restricting OVA-sensitized lung inflammation via promotion of IgG1 and inhibition of IgE class switching regulated by IL21 and STAT3.
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http://dx.doi.org/10.1186/s13052-021-01088-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314519PMC
July 2021

Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion.

Mol Hum Reprod 2021 08;27(8)

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.

Recurrent spontaneous abortion (RSA) is a common complication of early pregnancy. Dendritic cells (DCs) are thought to confer fetal-maternal immunotolerance and play a crucial role in ensuring a successful pregnancy. A decrease of plasmacytoid dendritic cells (pDCs) was found to be involved in RSA, but the underlying mechanisms of decreased pDC in RSA remain unclear. MicroRNAs (miRNAs) play critical roles in RSA as well as the development, differentiation and functional regulation of pDCs; however, the regulatory effect of miRNAs on pDC in RSA has not been fully investigated. Here we demonstrated that both the proportion of pDC and signal transducer and activator of transcription (STAT3)/transcription factor 4 (Tcf4/E2-2) expression decreased in the peripheral blood mononuclear cells and decidua of patients with RSA compared to those with normal pregnancy (NP), and there was a significantly positive correlation between pDC and STAT3 mRNA. MiRNA microarray assay and quantitative reverse transcription PCR results showed that miR-6875-5p expression was markedly increased in women with RSA and negatively correlated with mRNA expression level of STAT3. Up-regulated miR-6875-5p could sensitively discriminate patients with RSA from NP subjects. Overexpression of miR-6875-5p significantly down-regulated the mRNA expression of STAT3 and E2-2 as well as the protein and phosphorylation level of STAT3, while miR-6875-5p knockdown showed opposite results. Dual luciferase reporter verified that miR-6875-5p regulated STAT3 expression by directly binding to its 3'untranslated region. Overall, our results suggested that increased miR-6875-5p is involved in RSA by decreasing the differentiation of pDCs via inhibition of the STAT3/E2-2 signaling pathway. miR-6875-5p may be explored as a promising diagnostic marker and therapeutic target for RSA.
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http://dx.doi.org/10.1093/molehr/gaab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355038PMC
August 2021

Concurrent Chemoradiation Therapy With or Without Nimotuzumab in Locally Advanced Squamous Cell Lung Cancer: A Phase 2 Randomized Trial.

Int J Radiat Oncol Biol Phys 2021 Jul 3. Epub 2021 Jul 3.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; GuangDong Association Study of Thoracic Oncology, Guangzhou, Guangdong, China. Electronic address:

Purpose: The study aimed to evaluate the efficacy and safety of concurrent chemoradiation therapy (CCRT) combined with nimotuzumab in patients with unresectable stage III squamous cell lung cancer (SqCLC).

Methods And Materials: A prospective, single-center, open-label, randomized phase 2 trial was performed in patients with unresectable stage III SqCLC. Patients were randomized to receive 65 Gy thoracic radiation over 5 weeks concurrent with docetaxel and cisplatin or the same CCRT regimen combined with 200 mg of nimotuzumab (NIMO-CCRT), administered weekly by intravenous infusion. The primary endpoint was overall survival. The secondary endpoints were progression-free survival, objective response rate, failure patterns, and treatment-related toxicity.

Results: From August 2015 to June 2020, 126 patients with SqCLC were randomized. Four patients withdrew consent before the start of treatment, and 122 patients were included for analysis, including 57 in the NIMO-CCRT group and 65 in the CCRT group. The median OS was 24.9 months in the NIMO-CCRT group and 23.5 months in the CCRT group (P = .655). The median PFS was 12.1 months in the NIMO-CCRT group and 13.7 months in the CCRT group (P = .968). The NIMO-CCRT group had a significantly lower risk of brain metastasis, with adjusted subdistribution hazard ratio of 0.099 (95% confidence interval, 0.012-0.81; P = .031). The incidence of grade ≥3 pneumonitis (P = .894) and esophagitis (P = .974) was similar between the 2 arms. There was no grade 2 or higher skin toxicity in NIMO-CCRT group.

Conclusions: The coincident application of nimotuzumab with CCRT was well tolerated for locally advanced SCCL. The NIMO-CCRT group had an OS and PFS similar to that in the CCRT group, but a lower risk of brain metastasis. Further investigations are warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.032DOI Listing
July 2021

Exposure to isomers of per- and polyfluoroalkyl substances increases the risk of diabetes and impairs glucose-homeostasis in Chinese adults: Isomers of C8 health project.

Chemosphere 2021 Sep 5;278:130486. Epub 2021 Apr 5.

Guangdong Provincial Engineering Technology Research Center of Environmental Pollution and Health Risk Assessment, Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address:

Per- and polyfluoroalkyl substances (PFAS) exposure has been linked to diabetes, but evidence on the association of isomers of PFAS with type 2 diabetes (T2D) remains scant. This population based cross-sectional study aimed to investigate associations between serum PFAS isomers, glucose-homeostasis markers and T2D, adjusted for multiple potential confounders. We used data from "Isomers of C8 Health Project in China" from July 2015 to October 2016. A total of 10 PFAS including isomers of PFOS and PFOA were measured in serum of 1045 Chinese adults. Fasting blood glucose, fasting insulin, homeostasis model of insulin (HOMA-IR) and beta cell function (HOMA-β) were considered as markers of glucose-homeostasis. We found significant positive associations between serum PFAS isomers and glucose-homeostasis markers, namely, fasting blood glucose, fasting insulin and HOMA-IR. Per log-unit increase in branched (br)-PFOS concentration was associated with increased fasting blood glucose (β = 0.25, 95% CI: 0.18, 0.33), fasting insulin (β = 2.19, 95% CI: 1.44, 2.93) and HOMA-IR (β = 0.69, 95% CI: 0.50, 0.89). As compared to br-PFOS, linear (n)-PFOS and -PFOA showed lesser significant associations with glucose-homeostasis makers. Further, exposure to all PFAS including isomeric PFOS, PFOA and PFHxS increased the risk of T2D with br-PFOS exhibiting the highest risk (OR = 5.41, 95% CI: 3.68-7.96). The associations were stronger among women than men. In conclusion, chronic exposure to PFAS isomers was associated with impaired glucose-homeostasis and may increase the prevalence of T2D in Chinese adults. Given the ubiquity of PFAS in the environment and the public health burden of T2D, future studies are warranted to corroborate the findings.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130486DOI Listing
September 2021

MiR-19a-3p Suppresses M1 Macrophage Polarization by Inhibiting STAT1/IRF1 Pathway.

Front Pharmacol 2021 4;12:614044. Epub 2021 May 4.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.

Macrophages, an important type of immune cells, are generally polarized to classically activated macrophage (M1) or alternatively activated macrophage (M2) to respond to environmental stimuli. Signal transducer and activator of transcription 1 (STAT1), a very important transcription factor, can promote M1 macrophage polarization. However, the mechanisms of regulating STAT1 in macrophage polarization remain unclear. In the present study, STAT1 was markedly elevated, however, miR-19a-3p was down-regulated in interferon (IFN)-γ and lipopolysaccharide (LPS) treated RAW264.7 cells, and dual-luciferase reporter assay identified that miR-19a-3p directly targeted STAT1 by binding to its 3'UTR. Up-regulated miR-19a-3p inhibited M1 polarization by targeting STAT1/interferon regulatory factor 1 (IRF1) and vice versa . Consistently, overexpression of miR-19a-3p in LPS treated mice by systemically administering agomiR-19a-3p effectively reduced the inflammation in mouse lung tissues, and inhibited M1 macrophage polarization via suppressing STAT1/IRF1 pathway. In summary, our study confirmed that miR-19a-3p, as a direct regulator of STAT1, inhibited M1 macrophages polarization. The miR-19a-3p/STAT1/IRF1 pathway can potentially be used to design novel immunotherapy for modulating macrophage polarization.
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http://dx.doi.org/10.3389/fphar.2021.614044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129022PMC
May 2021

Moderately Hypofractionated Once-Daily Compared With Twice-Daily Thoracic Radiation Therapy Concurrently With Etoposide and Cisplatin in Limited-Stage Small Cell Lung Cancer: A Multicenter, Phase II, Randomized Trial.

Int J Radiat Oncol Biol Phys 2021 10 13;111(2):424-435. Epub 2021 May 13.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Lung Cancer Institute of Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China. Electronic address:

Purpose: Chemotherapy and concurrent thoracic radiation therapy (CCTRT) followed by prophylactic cranial irradiation (PCI) is the standard of care for limited-stage small cell lung cancer (LS-SCLC). We aimed to compare the efficacy and toxicity of moderately hypofractionated once-daily CCTRT with that of a standard twice-daily regimen.

Methods And Materials: This multicenter, phase 2, randomized study enrolled patients aged 18 to 75 years old who had pathologically confirmed LS-SCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received 4 to 6 cycles of etoposide-cisplatin chemotherapy and were randomized to receive twice-daily CCTRT at 45 Gray (Gy) in 30 fractions or once-daily CCTRT at 65 Gy in 26 fractions, commencing with cycles 1 to 3 of chemotherapy. PCI was given to good responders. The primary endpoint was progression-free survival (PFS).

Results: The analyses included 182 patients, with 94 in the twice-daily group and 88 in the once-daily group. CCTRT started with cycle 3 of chemotherapy for most patients (80.2%). At a median follow-up of 24.3 months, the median PFS was 13.4 months (95% confidence interval [CI], 10.8-16.0) in the twice-daily group versus 17.2 months (95% CI, 11.8-22.6) in the once-daily group (P = .031), with 2-year PFS rates of 28.4% (95% CI, 18.2-38.6) and 42.3% (95% CI, 31.1-53.5), respectively. The estimated overall survival was 33.6 months in the twice-daily group versus 39.3 months in the once-daily group (P = .137). The median locoregional PFS was 23.9 months in the twice-daily group and was not reached in the once-daily group (P = .017). The incidences of most toxicities were similar in both groups, except for a higher incidence of ≥grade 3 acute lymphopenia in the once-daily group (71.7% vs 40.2% in the twice-daily group; P < .001). There was no difference in the incidences of ≥grade 3 esophagitis (17.4% vs 15.3%, respectively), pneumonitis (3.3% vs 2.4%, respectively) or treatment-related death (2.2% vs 1.2%, respectively) between the once-daily and twice-daily groups.

Conclusions: Moderately hypofractionated, once-daily CCTRT showed improved PFS and similar toxicities compared with twice-daily CCTRT in LS-SCLC. This regimen should be evaluated for comparison in a phase 3 randomized trial.
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http://dx.doi.org/10.1016/j.ijrobp.2021.05.003DOI Listing
October 2021

Associations of perfluorooctane sulfonate alternatives and serum lipids in Chinese adults.

Environ Int 2021 10 30;155:106596. Epub 2021 Apr 30.

Guangdong Provincial Engineering Technology Research Center of Environmental Pollution and Health Risk Assessment, Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Background: Chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs), a group of perfluorooctane sulfonate (PFOS) alternatives, can be widely observed in humans and environmental matrices. However, associations between exposure to Cl-PFESAs and serum lipid levels in adults are unknown.

Objective: To explore the relationships between Cl-PFESA levels and serum lipid levels in adults.

Methods: We analyzed 1238 adults from the Isomers of C8 Health Project, a cross-sectional study conducted in China from July 2015 to October 2016. The average age of the participants was 61.98 ± 14.40 years. We quantified two select legacy per- and perfluoroalkyl substances [perfluorooctanoic acid (PFOA) and PFOS] and their alternatives (6:2 and 8:2 Cl-PFESAs). We also measured four serum lipids: low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). We used generalized linear models to estimate the associations between PFASs and serum lipids, with PFASs defined as either a categorical variable divided into quartiles or as a continuous variable.

Results: We found that 6:2 Cl-PFESA was positively associated with serum TC and LDL-C. For instance, LDL-C levels in the highest quartile of 6:2 Cl-PFESA exposure (Q4) were significantly higher than those in the lowest quartile (Q1) [β: 0.19, 95% confidence interval (CI): 0.08, 0.30]. Further analysis showed that one ln-ng/mL increase in 6:2 Cl-PFESA exposure corresponded to a 0.10 mmol/L (95% CI: 0.05, 0.16) LDL-C increase, and that exposure to 8:2 Cl-PFESA was negatively correlated with HDL-C (β: -0.03, 95% CI: -0.05, -0.01). TC had a similar relationship with both 6:2 Cl-PFESA and legacy PFASs. Participants with a BMI ≥ 25 kg/m exhibited a stronger association between 6:2 Cl-PFESA and TC.

Conclusions: Our findings make the novel suggestion that exposure to Cl-PFESAs are adversely associated with serum lipid levels, and that such associations are also observed in legacy PFASs. Increased investigation into the effects of Cl-PFESAs exposure on human health is warranted.
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http://dx.doi.org/10.1016/j.envint.2021.106596DOI Listing
October 2021

Hypo-fractionated radiotherapy with concurrent chemotherapy for locoregional recurrence of non-small cell lung cancer after complete resection: A prospective, single-arm, phase II study (GASTO-1017).

Lung Cancer 2021 06 27;156:82-90. Epub 2021 Apr 27.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Lung Cancer Institute of Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China. Electronic address:

Objectives: To explore the efficacy and toxicities of split-course hypo-fractionated radiotherapy with concurrent chemotherapy (HFRT-CHT) with intensity modulated radiotherapy (IMRT) technique in non-small cell lung cancer (NSCLC) patients with postoperative locoregional recurrence (LRR).

Materials And Methods: NSCLC patients were eligible if confirmed as LRR disease without distant metastasis after complete resection. HFRT-CHT using IMRT technique was administered with 51 Gy in 17 fractions or 40 Gy in 10 fractions as the first course followed by a break. Patients with no disease progression and no persistent Grade ≥2 toxicities had the second course of 15 Gy in 5 fractions or 28 Gy in 7 fractions as a boost. The primary endpoint was progression-free survival (PFS).

Results: Fifty-eight patients were enrolled and analyzed. With a median follow-up of 23.9 months for all, the 2-year and 3-year PFS rate was 59.7 % and 46.4 %, the 2-year and 3-year OS rate was 72.5 % and 52.2 %, respectively, and a favorable objective response rate of 95.9 % was obtained after the whole courses protocol. Grade 3 acute pneumonitis and esophagitis occurred in 2 (3.4 %) and 7 (12.1 %) patients, and fatal pneumonitis was reported in one case (1.7 %). Exploratory subgroup analysis showed that performance status (PS) (PS 0 vs. 1: 2-year PFS, 88.1 % vs. 46.9 %,P = 0.001; 2-year OS, 100 % vs. 59.4 %, P < 0.001), recurrence site (single vs. multiple: 2-year PFS, 93.8 % vs. 47.4 %, P = 0.008; 2-year OS, 100 % vs. 63.0 %, P = 0.001), and gross tumor volume (GTV) (<50cm vs. ≥ 50cm: 2-year PFS, 70.6 % vs. 46.2 %, P = 0.024; 2-year OS, 85.6 % vs. 57.4 %, P = 0.034) were significantly associated with PFS and OS.

Conclusion: Split-course HFRT-CHT with IMRT technique achieved promising disease control and satisfactory survival with moderate toxicities in postoperative LRR of NSCLC. Good PS, a single recurrence site and GTV<50cm tended to have prolonged PFS and OS. Early detection of LRR may improve the efficacy of HFRT-CHT.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.020DOI Listing
June 2021

Preparative separation of structural isomeric pentacyclic triterpenes from Eriobotrya japonica (Thunb.) leaves by high speed countercurrent chromatography with hydroxypropyl-β-cyclodextrin as additive.

J Chromatogr A 2021 Jun 15;1646:462066. Epub 2021 Mar 15.

College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China. Electronic address:

Maslinic acid and corosolic acid with high purity were successfully separated from Eriobotrya japonica (Thunb.) leaves by two-step countercurrent chromatographic separation. Two biphasic solvent systems composed of petroleum ether-ethyl acetate-ethanol-water (6:4:5:5, v/v) and petroleum ether-ethyl acetate-ethanol-0.10 mol/L of hydroxypropyl-β-cyclodextrin with pH 7.0 (8:2:3.5:6.5, v/v) were selected according to the partition performance of the main structural isomeric pentacyclic triterpenes. The influences of pH value and concentration of hydroxypropyl-β-cyclodextrin in separation of two isomers were investigated. In first step countercurrent chromatographic separation, a mixture of two target structural isomers (14.12 mg of sample I) was separated from 40.00 mg of a partially purified sample. In second step countercurrent chromatographic separation, maslinic acid and corosolic acid were completely isolated from 12.00 mg of sample I with hydroxypropyl-β-cyclodextrin as aqueous phase additive. The recoveries of the two isomers were over 90%, yielding 5.18 mg of maslinic acid and 5.47 mg of corosolic acid, respectively.
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http://dx.doi.org/10.1016/j.chroma.2021.462066DOI Listing
June 2021

Perfluorooctane sulfonate alternatives and metabolic syndrome in adults: New evidence from the Isomers of C8 Health Project in China.

Environ Pollut 2021 Aug 3;283:117078. Epub 2021 Apr 3.

Guangdong Provincial Engineering Technology Research Center of Environmental Pollution and Health Risk Assessment, Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address:

Chlorinated polyfluoroalkyl ether sulfonates (Cl-PFESAs), are ubiquitous alternatives to perfluorooctane sulfonate (PFOS), a widely used poly- and perfluoroalkyl substance (PFAS). Despite in vivo and in vitro evidence of metabolic toxicity, no study has explored associations of Cl-PFESAs concentrations with metabolic syndrome (MetS) in a human population. To help address this data gap, we quantified 32 PFAS, including 2 PFOS alternative Cl-PFESAs (6:2 and 8:2 Cl-PFESAs) in serum from 1228 adults participating in the cross-sectional Isomers of C8 Health Project in China study. The odds ratios (ORs) and 95% confidence intervals (CIs) of MetS and its various components were estimated using individual PFAS as a continuous or categorical predictor in multivariate regression models. The association between the overall mixture of PFAS and MetS was examined using probit Bayesian Kernel Machine Regression (BKMR-P). Greater serum PFAS concentrations were associated with higher odds of MetS and demonstrated a statistically significant dose-response trend (P for trend < 0.001). For example, each ln-unit (ng/mL) increase in serum 6:2 Cl-PFESA was associated with a higher prevalence of MetS (OR = 1.52, 95% CI: 1.25, 1.85). MetS was also 2.26 (95% CI: 1.59, 3.23) times more common in the highest quartile of serum 6:2 Cl-PFESA concentration than the lowest, and particularly high among women (OR = 6.41, 95% CI: 3.65, 11.24). The BKMR-P analysis showed a positive association between the overall mixture of measured PFAS and the odds of MetS, but was only limited to women. While our results suggest that exposure to Cl-PFESAs was associated with MetS, additional longitudinal studies are needed to more definitively address the potential health concerns of these PFOS alternatives.
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http://dx.doi.org/10.1016/j.envpol.2021.117078DOI Listing
August 2021

Establishment of deep eutectic solvent assisted matrix solid-phase dispersion extraction for the determination of four flavonoids in Scutellariae Radix based on the concept of quality by design.

J AOAC Int 2021 Mar 28. Epub 2021 Mar 28.

College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, P. R. China.

Background: Sample preparation is the most crucial step in the whole analytical schemes. Micro matrix solid-phase dispersion, as a method for microextraction of analytes, has prevailed recently for its low sample and extraction solvent consumption. However, small amount of adsorbent, sample or short extraction time always brings uncertainty on the result when using this method.

Objective: To develop a simple and reliable method by deep eutectic solvents assisted ultrasonic-synchronized matrix solid-phase dispersion microextraction for the analysis of four flavonoids in Scutellariae Radix based on the concept of quality by design.

Methods: Molecular sieve ZSM-5 was used as new adsorbent in MSPD process. Single factor and Box-Behnken design were used to construct the design space.

Results: Verification of experiment demonstrated that the design space is robust. Under the optimal conditions, all analytes showed good linearity (R2 > 0.999), high reproducibility (RSD < 2.24%) and stability (RSD < 2.87%), satisfactory recoveries (95.90∼102.31%), which indicated that the established method is reliable and reproducible. Moreover, it has been successfully applied to determine the flavonoids in nine batches of Scutellariae Radix.

Conclusion: The result indicated a great potential on analyzing precious complicated samples and helps to promote the quality control of the sample preparation process of traditional Chinese medicines.

Highlights: A systematic approach by using a facile DES assisted ultrasonic-synchronized matrix solid-phase dispersion extraction coupled with HPLC for the analysis of flavonoids in Scutellariae Radix has been developed based on the concept of quality by design.
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http://dx.doi.org/10.1093/jaoacint/qsab043DOI Listing
March 2021

Effects of surgery on survival of patients aged 75 years or older with oral tongue squamous cell carcinomas.

Sci Rep 2021 03 16;11(1):6003. Epub 2021 Mar 16.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.

The objective of this study is to assess prognostic value of surgery for elderly oral tongue squamous cell carcinomas (OTSCC) patients. Patients with OTSCC were extracted from the SEER database between 2010 and 2014. The distributions of categorical demographic and clinicopathological characteristics were determined for different age groups: the 75-79, 80-84, and 85-102 years old groups. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. A total of 1064 patients were analyzed. 75-79 years old patients tended to be male and rate of surgery declined with advancing age (P < 0.001). 75-79 years old patients more frequently presented with advanced stage compared to their older peers (P = 0.002). Compared to surgery groups, the hazard ratios for no surgery groups were 2.856 (95% CI 2.267-3.599; (P < 0.001)) for OS and 3.687 (95% CI 2.561-5.308; (P < 0.001)) for CSS in multivariable analysis. In subgroup analysis, the effect of no surgery was significantly associated with a higher risk of poor CSS in patients aged 75-79 years, 80-84 years and 85-102 years (P < 0.001, respectively). Our results showed that there were a series of factors contributing to poor outcomes in the elderly OTSCC patients, including clinicopathological characteristics and surgical management. Surgical resection is significantly associated with an improved OS and CSS, but further exploration in larger prospective clinical trials and better prognostic and predictive tools for select old patients for surgery are needed.
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http://dx.doi.org/10.1038/s41598-021-85647-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966770PMC
March 2021

Clinical warning of hemophagocytic syndrome caused by Epstein-Barr virus.

Ital J Pediatr 2021 Jan 7;47(1). Epub 2021 Jan 7.

Department of Infectious Disease, Children's Hospital of Soochow University, Suzhou, 215003, China.

Objectives: This study aimed to compare the clinical features and laboratory tests of infectious mononucleosis (IM) and hemophagocytic syndrome (HLH) caused by Epstein-Barr virus (EBV) in 1-3-year-old children and to explore the risk factor of HLH caused by EBV (EBV-HLH).

Methods: The clinical data of 92 children with EBV infection admitted in our hospital from 2011 to 2019 were collected; 61 cases were diagnosed as EBV-IM, and 31 cases were diagnosed as EBV-HLH. The subjects' clinical manifestations and laboratory tests were analyzed retrospectively.

Results: Compared with EBV-IM patients, EBV-HLH patients had longer durations of fever, both before hospitalization and overall, and a higher probability of hepatomegaly. The levels of ALT, AST, LDH, TG, SF, D-Dimer and the plasma EBV DNA load of EBV-HLH patients were significantly higher than those of EBV-IM patients. The absolute values of CD3, CD4, CD8, NK, and CD3-CD19 cells and IgA and IgM levels of EBV-HLH patients were significantly lower than those of EBV-IM patients. The plasma EBV DNA load was positively correlated with the PT, TT, α-HBDH, AST, LDH, CK, Scr, BUN, UA, TG, and CRP levels in EBV-HLH patients, and the plasma EBV DNA load was positively correlated with the D-Dimer level in the EBV-IM patients. Among the 10 different potential markers, at the cut-off point of 1721.500 μg/L, the sensitivity and specificity of D-Dimer was 88.90 and 90.20%, respectively.

Conclusion: The D-Dimer level may be a good prognostic indicator of EBV-HLH caused by EBV.
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http://dx.doi.org/10.1186/s13052-020-00949-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788532PMC
January 2021

Plasma vitrification and heavy metals solidification of MSW and sewage sludge incineration fly ash.

J Hazard Mater 2021 04 9;408:124809. Epub 2020 Dec 9.

School of Environmental Science and Engineering, Tianjin Key Lab of Biomass Waste Utilization, Tianjin University, Tianjin 300050, China; School of Mechanical Engineering, Tianjin University of Commerce, Tianjin 300134, China. Electronic address:

Thermal plasma treatment has been considered as one of promising methods for fly ash disposal. In this study, firstly, the characteristics of municipal solid waste incineration (MSWI) fly ash and sewage sludge incineration (SSI) fly ash were analyzed, followed by the raw material formulations of low melting temperature determined by thermodynamic equilibrium calculation. Then verified experiments were carried out by thermal plasma system, focused on the formation condition of vitrified slags with various CaO-SiO-AlO ratios and the influence factors of heavy metals (Cd, Cr, Ni, Pb, Zn, Cu) transference. According to the results: During the co-treatment process of fly ashes, a lower temperature of vitrified slag formation as low as 1230 ℃ was observed. Vitrification is determined by the molten phase content during melting process, the correlation coefficient between the glass phase content of slag and the molten phase content was 0.81 (P < 0.01). CaO content of raw materials was a major element for the volatilization of Cd and Pb. High AlO content can remain more Cr, Cu and Ni in slags, but it is not conducive to the solidification of Zn. The synthetic toxicity index of heavy metals would greatly reduce from 23153.15 to 663.29-820.63 after thermal plasma treatment.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124809DOI Listing
April 2021

Dendritic cells in pregnancy and pregnancy-associated diseases.

Biomed Pharmacother 2021 Jan 28;133:110921. Epub 2020 Nov 28.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China. Electronic address:

Dendritic cells (DCs) play a critical immuno-modulating role in pregnancy, which requires the maternal immune system to tolerate semiallogeneic fetus and at the same time to maintain adequate defense against pathogens. DCs interact closely with other immune components such as T cells, natural killer cells and macrophages, as well as the endocrine system to keep a pregnancy-friendly environment. Aberrant DC activities have been related to various pregnancy-associated diseases such as recurrent spontaneous abortion, preterm birth, pre-eclampsia, peripartum cardiomyopathy and infectious pregnancy complications. These findings make DCs an attractive candidate for prevention or therapy on the pregnancy-associated diseases. Here, we review recent findings that provide new insights into the roles of DCs in pregnancy and the related diseases. We also discuss the medical potentials to manipulate DCs in clinics. Whereas this is an emerging area with much work remaining, we anticipate that a better understanding of the role of DCs in maternal-fetal immunotolerance and a therapeutic manipulation of DCs will help women suffering from the pregnancy-associated diseases.
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http://dx.doi.org/10.1016/j.biopha.2020.110921DOI Listing
January 2021

A dual preconcentration method by combining micro matrix solid-phase dispersion extraction with field-enhanced sample injection and micelle to cyclodextrin stacking for sensitive analysis of neutral coumarins.

Electrophoresis 2021 May 1;42(9-10):1102-1107. Epub 2021 Feb 1.

College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, P. R. China.

A rapid, sensitive, environmental friendly dual preconcentration method by combining micro matrix solid-phase dispersion extraction with field-enhanced sample injection and micelle to cyclodextrin stacking has been developed for the determination of furocoumarins. Molecular sieve, KIT-6, was used as an adsorbent in micro matrix solid-phase dispersion process. The important parameters affecting off-line and online CE preconcentration efficiency were optimized. Under the optimal experimental conditions, all analytes showed good linearity (R > 0.999). The LODs of notopterol, isoimperatorin, and imperatorin were 0.1 μg/mL, 1.2 mg/kg, and 1.0 mg/kg, respectively. Compared with the normal CE method, the enrichment times were up to 300. Moreover, Angelicae Dahuricae Radix was used as the mode of complex solid sample matrix to demonstrate the prospect of application of this methodology. The results showed the proposed strategy is promising for determining trace furocoumarins in complex matrix samples, which might be applied as a powerful and economic tool in monitoring illegal cosmetic adding.
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http://dx.doi.org/10.1002/elps.202000273DOI Listing
May 2021

A Simple and Sensitive Dispersive Micro-Solid-Phase Extraction Coupled with High-Performance Liquid Chromatography for Quantification of Honokiol and Magnolol in Complex Matrices.

J AOAC Int 2020 Sep;103(5):1406-1411

College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, People's Republic of China.

Background: Honokiol and magnolol were considered as markers for the analysis of Cortex Magnoliae Officinalis, its related Chinese Patent Medicines and their metabolites. However, the determination of these two analytes in a water-soluble sample is difficult and therefore requires a more efficient method.

Objective: To develop a sensitive method for the determination of honokiol and magnolol in a water-soluble sample for better quality control of Cortex Magnoliae Officinalis and its related Chinese Patent Medicines.

Method: In this work, a combination of dispersive micro-solid-phase extraction (DMSPE) and high-performance liquid chromatography (HPLC) has been developed for simultaneous preconcentration and determination of honokiol and magnolol in complex bio-samples. Several experimental factors affecting the extraction efficiency were optimized by single factor test.

Results: Under the optimized extraction conditions, the proposed method exhibited good linearity of not less than 0.9998, satisfactory precision with relative standard deviation of less than 1.3%, and acceptable mean recoveries of 97.3% and 101.5% for honokiol and magnolol, respectively. Furthermore, the method exhibits extremely high sensitivity with detection limits of 0.0097 and 0.0231 ng/mL, which is even more sensitive than those methods developed by MS.

Conclusions: The method established in this study is fast, economic, accurate, easy to operate, and importantly well suited to the extraction and analysis of honokiol and magnolol in a real complex sample matrix.
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http://dx.doi.org/10.1093/jaoacint/qsaa049DOI Listing
September 2020

Personality Changes Predict Early Career Outcomes: Discovery and Replication in 12-Year Longitudinal Studies.

Psychol Sci 2021 01 23;32(1):64-79. Epub 2020 Nov 23.

Department of Psychology and Educational Psychology, University of Illinois at Urbana-Champaign.

In this research, we examined whether personality changes from adolescence to young adulthood predicted five early career outcomes: degree attainment, income, occupational prestige, career satisfaction, and job satisfaction. The study used two representative samples of Icelandic youth (Sample 1: = 485, Sample 2: = 1,290) and measured personality traits over 12 years (ages ~17 to 29 years). Results revealed that certain patterns of personality growth predicted career outcomes over and above adolescent trait levels and crystallized ability. Across both samples, the strongest effects were found for growth in emotional stability (income and career satisfaction), conscientiousness (career satisfaction), and extraversion (career satisfaction and job satisfaction). Initial trait levels also predicted career success, highlighting the long-term predictive power of personality. Overall, our findings show that personality has important effects on early career outcomes-both through stable trait levels and how people change over time. We discuss implications for public policy, for theoretical principles of personality development, and for young people making career decisions.
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http://dx.doi.org/10.1177/0956797620957998DOI Listing
January 2021

Associations between serum isomers of perfluoroalkyl acids and metabolic syndrome in adults: Isomers of C8 Health Project in China.

Environ Res 2021 05 9;196:110430. Epub 2020 Nov 9.

Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address:

Background: Exposure to perfluoroalkyl acids (PFAAs) is known to be associated with metabolic disorders. However, whether PFAAs isomers are associated with metabolic syndrome (MetS) still remains unknown.

Objectives: To explore the associations between serum PFAAs isomers and MetS.

Methods: We recruited 1,501 adults from a cross-sectional study, the "Isomers of C8 Health Project in China" to investigate the associations between PFAAs isomers and MetS. A total of 20 PFAAs including the isomers of PFOS and PFOA were detected. Logistic regression models and restricted cubic spline models were used to evaluate the relationship of serum PFAAs isomers exposure with MetS and its components as well after adjusting for covariates.

Results: The MetS prevalence in our study was 43.0%. The serum levels of both PFOS and PFOA isomers were higher in participants with MetS than that with non-MetS (p < 0.05). We found positive associations for per natural log-transformed ng/mL of branched perfluorooctane sulfonate (br-PFOS) (odds ratio (OR) = 1.18, 95% confidence interval (CI): 1.01, 1.38)) linear perfluoronanoic acid (n-PFOA) (OR = 1.35, 95% CI: 1.16, 1.58) and perfluoro-6-methylpheptanoic acid (6 m-PFOA) (OR = 1.32, 95% CI: 1.11, 1.57) with higher odds of MetS after covariates adjustment, while null association was observed for linear isomers of PFOS (OR = 1.09, 95% CI: 0.94, 1.25). We found a nonlinear dose-response relationship with a "threshold" effect in serum br-PFOS isomers with MetS, in which the odds of MetS increased quickly with increasing serum br-PFOS isomers under low exposure (p for nonlinearity = 0.030).

Conclusion: We report new evidence of associations between PFAAs isomers and MetS and the nonlinearity of dose-response relationship with br-PFOS isomers. Our findings indicate that more attention is needed to pay on the nonlinearity of dose-response relationship when investigate the association of PFAAs isomers with human health.
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http://dx.doi.org/10.1016/j.envres.2020.110430DOI Listing
May 2021

Meta-analysis based gene expression profiling reveals functional genes in ovarian cancer.

Biosci Rep 2020 11;40(11)

Department of Oncology, Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, No. 18877 Jingshi Road, Jinan 250062, China.

Background: Ovarian cancer causes high mortality rate worldwide, and despite numerous attempts, the outcome for patients with ovarian cancer are still not well improved. Microarray-based gene expressional analysis provides with valuable information for discriminating functional genes in ovarian cancer development and progression. However, due to the differences in experimental design, the results varied significantly across individual datasets.

Methods: In the present study, the data of gene expression in ovarian cancer were downloaded from Gene Expression Omnibus (GEO) and 16 studies were included. A meta-analysis based gene expression analysis was performed to identify differentially expressed genes (DEGs). The most differentially expressed genes in our meta-analysis were selected for gene expression and gene function validation.

Results: A total of 972 DEGs with P-value < 0.001 were identified in ovarian cancer, including 541 up-regulated genes and 431 down-regulated genes, among which 92 additional DEGs were found as gained DEGs. Top five up- and down-regulated genes were selected for the validation of gene expression profiling. Among these genes, up-regulated CD24 molecule (CD24), SRY (sex determining region Y)-box transcription factor 17 (SOX17), WFDC2, epithelial cell adhesion molecule (EPCAM), innate immunity activator (INAVA), and down-regulated aldehyde oxidase 1 (AOX1) were revealed to be with consistent expressional patterns in clinical patient samples of ovarian cancer. Gene functional analysis demonstrated that up-regulated WFDC2 and INAVA promoted ovarian cancer cell migration, WFDC2 enhanced cell proliferation, while down-regulated AOX1 was functional in inducing cell apoptosis of ovarian cancer.

Conclusion: Our study shed light on the molecular mechanisms underlying the development of ovarian cancer, and facilitated the understanding of novel diagnostic and therapeutic targets in ovarian cancer.
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http://dx.doi.org/10.1042/BSR20202911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677829PMC
November 2020

miR-130b-3p regulates M1 macrophage polarization via targeting IRF1.

J Cell Physiol 2021 03 27;236(3):2008-2022. Epub 2020 Aug 27.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Polarized macrophages can be broadly classified into classically activated macrophages (M1) and alternatively activated macrophages (M2) in response to the microenvironment signals. Interferon regulatory factor 1 (IRF1) has been demonstrated to play a critical role in macrophage polarization. However, the mechanisms underlying the regulation of IRF1 expression in macrophage polarization still remain unclear. In this study, IRF1 expression was significantly increased in interferon-γ (IFN-γ) and lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, miR-130b-3p was decreased and negatively associated with Irf1 in M1 macrophages. miR-130b-3p repressed M1 polarization by inhibiting IRF1 and subsequently reducing the levels of the targets of IRF1, C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), inducible NO synthase (iNOS), and tumor necrosis factor (TNF). Consistent with these data, overexpressed miR-130b-3p in LPS-treated mice suppressed M1 macrophage polarization in lung macrophages and peritoneal macrophages by inhibiting Irf1 expression and alleviated the inflammation in mouse lung tissues. Furthermore, the predicted binding site between the Irf1 messenger RNA 3'-untranslated region (3'-UTR) and miR-130b-3p was confirmed by the dual-luciferase reporter assay. In conclusion, our research gave the first evidence that miR-130b-3p affected the polarization of M1 macrophages by directly inhibiting Irf1. The miR-130b-3p/IRF1 pathway may be a potential target for regulating macrophage polarization.
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http://dx.doi.org/10.1002/jcp.29987DOI Listing
March 2021

Honokiol-Chlorambucil Co-Prodrugs Selectively Enhance the Killing Effect through STAT3 Binding on Lymphocytic Leukemia Cells and .

ACS Omega 2020 Aug 29;5(31):19844-19852. Epub 2020 Jul 29.

Institute of Chinese Medicine, Hunan Academy of Traditional Chinese Medicine&Innovation Centre for Science and Technology, Hunan University of Chinese Medicine, Changsha 410208, PR China.

The broad-spectrum DNA alkylating therapeutic, chlorambucil (CBL), has limited safety and shows lower therapy effect because of a short half-life while used in the clinic. Therefore, it is very necessary to develop a more efficient and safer type of CBL derivate against tumors with selective targeting of cancer cells. In addition, the natural product of honokiol (HN), the novel potent chemo-preventive or therapeutic entity/carrier, can target the mitochondria of cancer cells through STAT3 to prevent cancer from spreading and metastasizing. In this study, we designed and synthesized the honokiol-chlorambucil (HN-CBL) co-prodrugs through carbonate ester linkage conjugating with the targeted delivery help of the HN skeleton in cancer cells. Biological evaluation indicated that HN-CBL can remarkably enhance the antiproliferation of human leukemic cell lines CCRF-CEM, Jurkat, U937, MV4-11, and K562. Furthermore, HN-CBL can also selectively inhibit the lymphocytic leukemia (LL) cell survival compared to those mononuclear cells derived from healthy donors (PBMCs), enhance mitochondrial activity in leukemia cells, and induce LL cell apoptosis. Molecular docking and western blot study showed that HN-CBL can also bind with the STAT3 protein at some hydrophobic residues and downregulate the phosphorylation level of STAT3-like HN. Significantly, HN-CBL could dramatically delay leukemia growth with no observable physiological toxicity. Thus, HN-CBL may provide a novel and effective targeting therapeutic against LL with fewer side effects.
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http://dx.doi.org/10.1021/acsomega.0c02832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424726PMC
August 2020

Generation of a Hutchinson-Gilford progeria syndrome monkey model by base editing.

Protein Cell 2020 11 29;11(11):809-824. Epub 2020 Jul 29.

Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, China.

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.
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http://dx.doi.org/10.1007/s13238-020-00740-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647984PMC
November 2020

Two new -lignans from (Hook. & Grev.) Maxim and their antihyperglycemic activities.

Nat Prod Res 2020 Jun 22:1-8. Epub 2020 Jun 22.

College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, P.R. China.

Two new -lignans, pulvin A () and moellenoside C (), along with two known compounds (-) were isolated from the whole plant of (Hook. & Grev.) Maxim. The structures of the new compounds were established on the basis of spectroscopic data and acid hydrolysis. All the isolates were investigated for their antihyperglycemic activities in 3T3-L1 adipocytes. The results showed that compounds and promoted the glucose consumption prominently in 3T3-L1 adipocytes in a dose-response manner. Compound and induced 1.14-1.73 folds and 1.03-1.55 folds changes relative to the basal level, respectively, in the concentration range of 12.5 μM to 50 μM.
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http://dx.doi.org/10.1080/14786419.2020.1779267DOI Listing
June 2020

MiR-103 protects from recurrent spontaneous abortion via inhibiting STAT1 mediated M1 macrophage polarization.

Int J Biol Sci 2020 25;16(12):2248-2264. Epub 2020 May 25.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 18877 Jingshi Road, Jinan 250062, Shandong, China.

Recurrent spontaneous abortion (RSA) is a common complication of early pregnancy. Excessive M1 macrophage was found to be involved in RSA, but the underlying mechanisms remains unclear. MicroRNAs play critical roles in RSA as well as the polarization of macrophages; however, the regulatory effect of miRNAs on M1 differentiation in RSA has not been fully investigated. In this study, miRNA microarray assay revealed that miR-103 was significantly decreased in RAW264.7-derived M1 macrophages upon IFNγ and LPS stimulation. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that in RSA patients, miR-103 expression was decreased substantially, and negatively correlated with that of STAT1. Moreover, down-regulation of miR-103 could sensitively discriminate RSA patients from normal pregnancies (NP) subjects. Experiments showed that overexpression of miR-103 suppressed M1 polarization by inhibiting STAT1/IRF1 signaling pathway and vice versa. miR-103 regulated STAT1 expression by direct binding to its 3'-UTR. Moreover, our study demonstrated that overexpressed miR-103 could reduce mice embryo resorption and M1 polarization effectively. Overall, the results suggested that decreased miR-103 was involved in RSA by increasing M1 macrophage polarization via promoting STAT1/IRF1 signaling pathway. miR-103 may be explored as a promising diagnostic marker and therapeutic target for RSA.
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http://dx.doi.org/10.7150/ijbs.46144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294935PMC
May 2020

miR-374b-5p is increased in deep vein thrombosis and negatively targets IL-10.

J Mol Cell Cardiol 2020 07 21;144:97-108. Epub 2020 May 21.

Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 18877 Jingshi Road, Jinan 250062, Shandong, China. Electronic address:

Background: Deep venous thrombosis (DVT) is one of the most common venous thromboembolic (VTE) disorders and the third leading cardiovascular complication. Accumulating evidence has shown that decreased interleukin-10 (IL-10) was involved in DVT. However, the underlying molecular mechanisms are still largely unknown. Here, we proposed that the epigenetic modification of IL-10 at the post-transcriptional level may be a crucial trigger for IL-10 down-regulation in DVT.

Methods: miRNA expression in DVT was profiled by miRNA microarray analysis. The upstream miRNA regulators of IL-10 were predicted by in silico target prediction tools. The expression of IL-10 mRNA and miR-374b-5p were examined by quantitative real-time PCR (qRT-PCR) and the protein expression of IL-10 was detected by enzyme-linked immunoassay. Dual luciferase reporter assay was used to identify the interaction between miR-374b-5p and IL10. A murine model of DVT was developed and the localization of miR-374b-5p was visualized in vitro by fluorescence in situ hybridization. The biological effects of miR-374b-5p on IL-10 was examined both in vitro and in vivo.

Results: Microarray and qRT-PCR results showed that the IL-10 expression was decreased while miR-374b-5p level was increased substantially in peripheral blood mononuclear cells of DVT patients, and there was significant negative correlation between miR-374b-5p and IL-10. Experiments in vitro showed that overexpressed miR-374b-5p reduced IL-10 expression, while miR-374b-5p knockdown increased IL-10 expression. Moreover, in vivo studies revealed that DVT mice with anti-IL-10 antibody or agomiR-374b-5p delivery resulted in decreased IL-10 expression and aggravated DVT formation, whereas antagomiR-374b-5p acted inversely. Dual luciferase reporter assay identified direct binding between miR-374b-5p and IL10.

Conclusions: These findings suggest that increased miR-374b-5p promotes DVT formation by downregulating IL-10 expression. miR-374b-5p may be explored as a promising diagnostic marker and therapeutic target for DVT.
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http://dx.doi.org/10.1016/j.yjmcc.2020.05.011DOI Listing
July 2020

Simultaneous determination of seven compounds in Chinese patent medicines Chenxiangqu by matrix solid-phase dispersion coupled with ultra high performance liquid chromatography and quadrupole time-of-flight mass spectrometry.

J Sep Sci 2020 Jul 25;43(14):2869-2879. Epub 2020 May 25.

College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, P. R. China.

A simple, efficient, and sensitive strategy by coupling matrix solid-phase dispersion with ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry was proposed to extract and determine three types of components (including seven analytes) in Chinese patent medicines Chenxiangqu. The highly ordered mesoporous material Fe-SBA-15 synthesized under weakly acidic conditions was selected as a dispersant in matrix solid phase dispersion extraction for the first time. Several parameters including the mass ratio of sample to dispersant, the type of dispersant, the grinding time, and the elution condition were investigated in this work. Under the optimized conditions, 20 compounds were identified by quadrupole time-of-flight mass spectrometry and seven analytes were quantified. The results demonstrated that the developed method has good linearity (r > 0.9995), and the limits of detection of the analytes were as low as 0.55 ng/mL. The recoveries of all seven analytes ranged from 97.6 to 104.6% (relative standard deviation < 3.4%). Finally, the improved method was successfully applied to determination of five batches of Chenxiangqu samples, which provided a robust method in quality control of Chinese patent medicines Chenxiangqu. The developed strategy also shows its great potential in analysis of complex matrix samples.
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http://dx.doi.org/10.1002/jssc.201901226DOI Listing
July 2020
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