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Wen Ting Zhu,1,* Xiang Feng Zeng,2,* Hua Yang,2 Meng Lei Jia,1 Wei Zhang,2 Wei Liu,2 Sheng Yao Liu3 1Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, People’s Republic of China; 2Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China; 3Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Liu, Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China, Email lwsurgery@163.com Sheng Yao Liu, Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China, Email liushengyao12@163.comBackground: Osteosarcoma is a malignant bone tumor with a high rate of lung metastasis and mortality. It has been demonstrated that resveratrol can inhibit tumor proliferation and metastasis, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare folate-modified liposomes loaded with resveratrol to investigate its anti-osteosarcoma effect in vitro and in vivo.Methods: We prepared and characterized resveratrol liposomes modified with folate (denoted as, FA-Res/Lps). The effects of FA-Res/Lps on human osteosarcoma cell 143B proliferation, apoptosis, and migration were investigated by MTT, cell cloning, wound-healing assay, transwell, and flow cytometry. A xenograft tumor and lung metastasis model of osteosarcoma was constructed to study the therapeutic effects of FA-Res/Lps on the growth and metastasis of osteosarcoma in vivo.Results: The FA-Res/Lps were prepared with a particle size of 118.5 ± 0.71 and a small dispersion coefficient of 0.154 ± 0.005. We found that FA-modified liposomes significantly increased resveratrol uptake by osteosarcoma cells 143B in flow cytometric assay, resulting in FA-Res/Lps, which inhibit tumor proliferation, migration and induce apoptosis more effectively than free Res and Res/Lps. The mechanism of action may be associated with the inhibition of JAK2/STAT3 signaling. In vivo imaging demonstrated that FA-modified DiR-modified liposomes significantly increased the distribution of drugs at the tumor site, leading to significant inhibition of osteosarcoma growth and metastasis by FA-Res/Lps. Furthermore, we found that FA-Res/Lps did not cause any adverse effects on mice body weight, liver, or kidney tissues.Conclusion: Taken together, the anti-osteosarcoma effect of resveratrol is significantly enhanced when it is loaded into FA-modified liposomes. FA-Res/Lps is a promising strategy for the treatment of osteosarcoma.Keywords: resveratrol, liposomes, osteosarcoma, lung metastasis, JAK2/STAT3 pathway

Xiao-Min Liu1 *, Wen-Ting Zhu1 *, Meng-Lei Jia,1 Yu-Ting Li,1 Ye Hong,1 Zhong-Qiu Liu,2 Peng-Ke Yan1 1Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Qiu Liu, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China, Email liuzq@gzucm.edu.cn Peng-Ke Yan, Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Email gysyypk@126.comBackground: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro.Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs.Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration.Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.Keywords: rapamycin liposomes, 5-fluorouracil, angiogenesis, APC (Min/+) mice, AOM/DSS, colorectal cancer

Yi-Qing Chen,* Wen-Ting Zhu,* Cai-Yan Lin, Zhong-Wen Yuan, Zhen-Hua Li, Peng-Ke Yan The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng-Ke YanThe Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of ChinaEmail gysyypk@126.comBackground: Rapamycin is a promising agent for treating tumors, but clinical applications of rapamycin are limited due to its poor water solubility and low bioavailability. This paper constructs a liposome delivery system for rapamycin to improve the effect in treating colorectal cancer.Methods: We prepared the rapamycin liposomes using the ethanol injection method. The cellular uptake and biodistribution were detected by LC-MS and in vivo imaging system. MTT assay, transwell migration experiment, flow cytometry, and Western blot analysis evaluated the antitumor effect of rapamycin liposomes in vitro. Furthermore, HCT-116 tumor-bearing mice were used to assess the therapeutic efficacy of rapamycin liposomes in vivo.Results: The prepared rapamycin liposomes had a particle size of 100± 5.5 nm and with a narrow size distribution. In vitro cellular uptake experiments showed that the uptake of rapamycin liposomes by colorectal cells was higher than that of free rapamycin. Subsequently, in vivo imaging experiments also demonstrated that rapamycin liposomes exhibited higher tumor accumulation. Therefore, the ability of rapamycin liposomes to inhibit tumor proliferation, migration and to induce tumor apoptosis is superior to that of free rapamycin. We also demonstrated in vivo good antitumor efficacy of the rapamycin liposomes in HCT-116 xenograft mice. In addition, rapamycin liposomes and 5-FU can synergistically improve the efficacy of colorectal cancer via the Akt/mTOR and P53 pathways.Conclusion: Collectively, rapamycin liposomes are a potential treatment for colorectal cancer, as it not only improves rapamycin’s antitumor effect but also synergistically enhances 5-FU’s chemotherapy effect.Keywords: rapamycin liposomes, 5-fluorouracil, Akt/mTOR, P53, colorectal cancer

Lian-Tao Li,1–3,* Xun Wang,4,* Wen-Tao Zhu,5,* Guo-Wei Qian,6 Dong-Sheng Pei,1,5 Jun-Nian Zheng1,2 1Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 2Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 3Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 4Department of Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 5Department of Pathology, Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 6Department of Medical Oncology, Shanghai Sixth People’s Hospital, Shanghai 200000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong-Sheng Pei; Jun-Nian Zheng 84 West Huaihai Road, Xuzhou, Jiangsu, People’s Republic of ChinaTel +8605168558230Email dspei@xzhmu.edu.cn; jnzheng@xzhmu.edu.cnPurpose: DNA methylation plays major regulatory roles in gene transcription. Our previous studies confirmed that Ki-67 promoter is hypomethylated and Sp1 is a transcriptional activator of Ki-67 gene in cancer cells. However, whether Sp1-mediated transcriptional activation of Ki-67 is related to its methylation has not been studied yet.Materials and methods: In this study, we confirmed that methylated CpG binding protein 2 (MBD2) binding to methylated DNA hindered the binding of Sp1 to Ki-67 promoter and then repressed Ki-67 transcription through chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR). Co-immunoprecipitation (Co-IP), ChIP, methylation-specific PCR (MS-PCR) and Western blot were utilized to analyze the effects of Sp1 binding to Ki-67 promoter on its methylation status.Results: Less DNA methyltransferase 1 (DNMT1) bound to the Ki-67 promoter in MKN45 cells than in HK-2 cells. Histone acetyltransferase p300 that was recruited by Sp1 to Ki-67 promoter could attenuate the methylation level of Ki-67 promoter. Furthermore, higher expression of Sp1 and Ki-67 was related to the overall survival (OS), first progression (FP) and post-progression survival (PPS) in gastric cancer by scrutinizing bioinformatics datasets.Conclusion: Taken together, our findings suggested that hypomethylation of Ki-67 promoter enhanced the binding of Sp1, which in turn maintained hypomethylation of promoter, leading to increase Ki-67 expression in cancer cells. Sp1 and Ki-67 could act promising prognostic biomarkers for clinical diagnosis and treatment of cancer.Keywords: methylation, Ki-67, Sp1, promoter, cancer

Ming Shao,1,* Weitao Zhu,2,* Xianping Lv,1 Qiankun Yang,1 Xin Liu,1 Ying Xie,1 Ping Tang,3 Ling Sun3 1Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China; 2Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China; 3Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China *These authors contributed equally to this work Purpose: As the deadliest gynecological malignancy, ovarian cancer ranks as a major cause of disease-related deaths to women worldwide and is treated with transurethral resection or systemic chemotherapy. However, traditional chemotherapeutic drug in antitumor therapy has shown unavoidable limitations, such as poor curative effects, systemic toxicity and development of drug resistance, leading to failure of tumor inhibition and recurrence. This study aims to explore an innovative method to enhance the clinical efficiency of ovarian cancer.Materials and methods: Using MTT assay, the cell viability was detected under different culture systems. Western blot was used to examine the expression of P-gp in doxorubicin-resistant and wild-type A2780/SKOV3 cells. We used confocal to examine the drug concentration under different culture conditions. Also, flow cytometry was used to detect the drug absorption at the determined time points under different culture systems. Using nude mice model, we evaluated the killing efficacy of chemotherapeutic drugs with or without nanoparticle encapsulation. ELISA was used to examine the levels of creatinine, alanine aminotransferase and aspartate aminotransferase in plasma.Results: We found that pretreatment of chloroquine (CQ) as chemosensitizer markedly enhanced the anticancer effects in ovarian cancer. We also provided evidence that CQ efficiently increase the pH value of lysosomes in tumor cells, leading to the reverse of drug sequestration induced by lysosomes. To further improve the pharmacokinetics profiles and avoid the systemic toxicity caused by chemotherapeutic agents, we encapsulated CQ and chemotherapeutic drugs by polymeric nanoparticles methoxy poly(ethylene glycol)-poly(L-lactic acid). Codelivery of CQ and chemotherapeutic agents by nanocarrier revealed enhanced anticancer effects compared with the free drug delivery by tail vein injection. More importantly, accumulated drugs, prolonged drug circulation and reduced organic damages were observed in nanoparticles delivery.Conclusion: Codelivery of CQ and chemotherapeutic drugs by methoxy poly(ethylene glycol)-poly(L-lactic acid) could significantly improve the anticancer effects and might have important potency in clinical applications for ovarian cancer therapy. Keywords: ovarian cancer, chloroquine, cisplatin, MPEG-PLA, nanoparticles

Wen-Ting Zhu,1,2,* Sheng-Yao Liu,3,* Lei Wu,1,2 Hua-Li Xu,4 Jun Wang,1,2 Guo-Xin Ni,3,5 Qing-Bing Zeng1,2 1Biomaterial Research Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; 2Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; 3Department of Orthopeadics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China; 4Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; 5Department of Rehabilitation Medicine, First Affiliated Hospital, Fujian Medical University, Fuzhou, China *These authors contributed equally to this work Background: It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. Materials and methods: In this study, CUR-loaded methoxy polyethylene glycol–polylactide (CUR/mPEG–PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. Results: The average size of CUR/mPEG–PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067–0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG–PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG–PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG–PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG–PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. Conclusion: The mPEG–PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG–PLA micelles have promising clinical potential in treating NSCLC. Keywords: curcumin, mPEG–PLA, polymeric micelles, A549 cells, HUVECs, angiogenesis

Xiaoyi Wang, Ying Wang, Xiaoyuan Feng, Ying Lu, Yu Zhang, Wenwen Wang, Wentao Zhu School of Management, Beijing University of Chinese Medicine, Beijing, People’s Republic of China Objective: The aim of the study was to evaluate the effectiveness, safety, and cost associated with Wenxin keli in the treatment of cardiovascular diseases based on meta-analysis. Methods: The terms “Wenxin keli” and “Wenxin” were used as the search terms in the PubMed, ProQuest, Springer, the Cochrane Library, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), and Wan fang electronic databases (from January 2000 to October 2015). Relevant print journals and conference papers were also searched. Studies on randomized controlled trials (RCTs) of Wenxin keli used in the treatment of cardiovascular diseases were screened, and its indications were classified. Meta-analysis of these studies was conducted using the RevMan 5.2 software. Results: A total of 49 RCTs (n=4,610) were included, 29 of which focused on arrhythmia, seven on angina, seven on heart failure, two on viral myocarditis, and four on menopausal syndrome. Analysis of the therapeutic indications of Wenxin keli showed that it was comparatively more curative and effective than other available treatments for cardiovascular diseases. Conclusion: Wenxin keli showed better clinical efficacy in the treatment of arrhythmia, angina, and heart failure; however, more high-quality evidence is needed to support its use in the clinical setting. Keywords: Wenxin keli, cardiovascular disease, meta-analysis, systematic review

This study is to demonstrate the protection of atractylenolide III (AT III) on intestinal barrier dysfunction in ulcerative colitis (UC). UC model was established by 3% dextran sulfate sodium (DSS), and TNF-α was used to induce dysfunction in the intestinal epithelial barrier. TEER, FD-4 transmembrane flux and DAI were measured. Histopathological changes was identified by H&E staining, TJ structure changes were observed by TEM, IL-1β and TNF-α contents were measured by ELISA, bacterial translocation was investigated by FISH. The expressions of ZO-1, occludin, and the proteins in the MLCK/p-MLC and NF-κB pathways were analyzed by Western blotting or immunofluorescence. The results indicated that AT III alleviate the symptoms of DSS-induced colitis, reduce the disruption of intestinal epithelial barrier, and decrease FD4. Moreover, AT III inhibited the destruction of intestinal epithelial TJ structure and bacterial translocation in UC mice. AT III reversed the high levels of IL-1β and TNF-α, the decrease of occludin, ZO-1 expressions. Furthermore, AT III showed similar effects to PDTC (pyrrolidinedithiocarbamate) in ameliorating the disruption of the TNF-α-induced TEER and FD-4 disruption, MLCK protein expression, and MLC2 phosphorylation. In conclusion, AT III mitigates the dysfunction of intestinal epithelial barrier in UC through the NF-κB-mediated MLCK/p-MLC signaling pathway., Competing Interests: Declaration of competing interest All the authors have seen the paper and approved the original. They have seen the paper and are in agreement with its content before the paper is submitted to the Editorial Office. The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Lymph node metastasis (LNM) is a typical marker in oral squamous cell carcinoma (OSCC) indicating poor prognosis. Pathological examination by artificial image acquisition and analysis, as the main diagnostic method for LNM, often takes a week or longer which may cause great anxiety of the patient and also retard timely treatment. However, there are few efficient fast LNM diagnosis methods in clinical applications currently. Our previous study profiled the proteomics of extracellular vesicles (EVs) derived from postoperative drainage fluid (PDF) and showed the potential of detecting specific EVs that expressed aspartate β-hydroxylase (ASPH) for LNM diagnosis in OSCC patients. Considering that the analysis of ASPH + PDF-EVs is challenging due to their low abundance (counting less than 10% of total EVs in PDF) and the complex EV isolation process of ultra-centrifugation, we developed a facile platform containing two microfluidic chips filled with antibody-modified microbeads to isolate ASPH + PDF-EVs, with both the capture and retrieval rate reaching around 90%. Clinical sample analysis based on our method revealed that a mean of 6 × 10 6 /mL ASPH + PDF-EVs could be isolated from LNM + OSCC patients compared to 2.5 × 10 6 /mL in LNM - OSCC ones. When combined with enzyme-linked immunosorbent assay (ELISA) technique that was commonly used in clinical laboratories in hospitals, this microfluidic platform could precisely distinguish postoperative OSCC patients with LNM or not in several hours, which were validated by a double-blind test containing 6 OSCC patients. We believe this strategy has promise for early diagnosis of LNM in postoperative OSCC patients and finally helps guiding timely and reasonable treatment in clinic., (© 2024. The Author(s).)

Background: RT-qPCR is a powerful strategy for recognizing the most appropriate reference genes, which can successfully minimize experimental mistakes through accurate normalization. Ludisia discolor , recognized for its ornamental value, features little, distinctive blossoms with twisted lips and gynostemium showing chiral asymmetry, together with striking blood-red fallen leaves periodically marked with golden blood vessels. Methods and Results: To ensure the accuracy of qRT-PCR, selecting appropriate reference genes for quantifying target gene expression levels is essential. This study aims to identify stable reference genes during the development of L. discolor . In this study, the entire floral buds, including the lips and gynostemium from different development stages, were taken as materials. Based upon the transcriptome information of L. discolor , nine housekeeping genes, ACT , HIS , EF1-α1 , EF1-α2 , PP2A , UBQ1 , UBQ2 , UBQ3 , and TUB , were selected in this research study as prospect interior referral genes. The expression of these nine genes were found by RT-qPCR and afterwards comprehensively examined by four software options: geNorm, NormFinder, BestKeeper, and ΔCt. The outcomes of the analysis showed that ACT was the most steady gene, which could be the most effective inner referral gene for the expression evaluation of flower advancement in L. discolor . Conclusions: The results of this study will contribute to the molecular biology research of flower development in L. discolor and closely related species.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-β1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV-HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-β1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-β1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD., (© 2024. The Author(s).)

Background: Recent evidence indicates that Shexiang Baoxin Pill (MUSKARDIA), as an add-on treatment to standard therapy for stable coronary artery disease (CAD), is effective. Nevertheless, the cost-effectiveness of introducing the Shexiang Baoxin Pill (Abbreviation SBP) to the current standard treatment for patients with CAD in China remains unknown., Objective: The objective of this study was to assess the cost-effectiveness of introducing SBP into the current standard treatment in China for patients with CAD., Method: The effects of two treatment strategies-the SBP group (SBP combined with standard therapy) and the standard therapy group (placebo combined with standard therapy)-were simulated using a long-term Markov model. The simulation subjects might experience non-fatal MI and/or stroke or vascular or non-vascular death events. The study parameters were primarily derived from the MUSKARDIA trial, which was a multicenter, double-blind, placebo-controlled phase IV randomized clinical trial. Furthermore, age-related change, event costs, and event utilities were drawn from publicly available sources. Both costs and health outcomes were discounted at 5.0% per annum. One-way and probabilistic sensitivity analyses were conducted to verify the robustness of the model. Based on the MUSKARDIA trial results, the risk with the events of major adverse cardiovascular events (MACE) was decreased (P < 0.05) in the female subgroup treated with SBP therapy compared with standard therapy. Consequently, a scenario analysis based on subgroups of Chinese females was conducted for this study. Incremental cost-effectiveness ratios (ICERs) were assessed for each strategy for costs per quality-adjusted life-year (QALY) saved., Results: After 30 years of simulation, the SBP group has added 0.32 QALYs, and the cost has been saved 841.00 CNY. Compared with the standard therapy, the ICER for the SBP therapy was -2628.13 CNY per QALY. Scenario analyses of Chinese females showed that, after 30 years of simulation, the SBP therapy has been increased by 0.82 QALYs, and the cost has been reduced by 19474.00 CNY. Compared with the standard therapy, the ICER for the SBP therapy was -26569.51 CNY per QALY. Similar results were obtained in various extensive sensitivity analyses., Conclusions: This is the first study to evaluate the cost-effectiveness of SBP in the treatment of CAD. In conclusion, SBP as an add-on treatment to standard therapy appears to be a cost-effective strategy for CAD in Chinese patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Non-alcoholic steatohepatitis (NASH) is a global health problem with no effective treatment. Isoquercitrin (IQ) alters hepatic lipid metabolism and inhibits adipocyte differentiation. The underlying regulatory mechanisms of IQ in regulating insulin resistance (IR) and lipid metabolism remain unclear., Purpose: This study was aimed at investigating the effects of IQ on NASH and deciphering whether the underlying mechanisms are via modulation of galectin-3 mediated IR and lipid metabolism., Methods: IR-HepG2 cell lines were used to demonstrate the ability of IQ to modulate galectin-3-mediated glucose disposal and lipid metabolism. A 20-week high-fat diet (HFD)-induced NASH model was established in C57BL/6J mice, and the protective effect of IQ on lipid disposal in the liver was verified. Further, the mRNA and protein levels of glucose and lipid metabolism were investigated, and lysophosphatidylcholine (LPC) and acylcarnitine (AC) profiling were performed to characterize the changes in endogenous substances associated with mitochondrial function and lipid metabolism in serum and cells. Furthermore, the pharmacokinetic features of IQ were explored in a rat model of NASH., Results: IQ restored liver function and ameliorated inflammation and lipid accumulationin NASH model mice. Notably, significant regulation of the proteins included fatty acid-generating and transporting, cholesterol metabolism enzymes, nuclear transcription factors, mitochondrial metabolism, and IR-related enzymes was noted to be responsible for the therapeutic mechanisms of IQ against experimental NASH. Serum lipid metabolism-related metabolomic assay confirmed that LPC and AC biosynthesis mostly accounted for the therapeutic effect of IQ in mice with NASH and that IQ maintained the homeostasis of LPC and AC levels., Conclusion: This is the first study showing that IQ protects against of NASH by modulating galectin-3-mediated IR and lipid metabolism. The mechanisms responsible for liver protection and improved lipid metabolic disorder by IQ may be related to the suppression of IR and regulation of mitochondrial function and lipid metabolism. Galectin-3 down-regulation represents a potentially novel approach for the treatment and prevention of NASH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

This study aimed to examine the morphological, physiological, and biochemical alterations occurring in Notopterygium incisum seeds throughout their developmental stages, with the objective of establishing a theoretical foundation for the cultivation of superior quality seeds. The experimental materials utilized in this study were the seeds of N. incisum at various stages of development following anthesis. Through the employment of morphological observation and plant physiology techniques, the external morphology, nutrients, enzyme activity, and endogenous hormones of the seeds were assessed. The results revealed a transition in seed coat color from light green to brown during the growth and development of N. incisum seeds. Additionally, as the seeds matured, a decrease in water content was observed. Conversely, starch content exhibited a progressive increase, while sucrose content displayed fluctuations. At 7 days after anthesis, the soluble sugar content attained its highest level of 4.52 mg·g~(-1), whereas the soluble protein content reached its maximum of 6.00 mg·g~(-1) at 14 days after anthesis and its minimum of 4.94 mg·g~(-1) at 42 days after anthesis. The activity of superoxide dismutase(SOD) exhibited an initial increase, followed by a decrease, and eventually reached a stable state. Conversely, the activities of catalase(CAT) and peroxidase(POD) demonstrated a decrease initially, followed by an increase, and then another decrease. The levels of the four endogenous hormones, namely gibberellin(GA&#95;3), zeatin riboside(ZR), auxin(IAA), and abscisic acid(ABA), in the seeds displayed significant variations, with IAA and ABA exhibiting considerably higher levels compared to the other hormones. The levels of plant growth-promoting hormones, represented by IAA, generally displayed a pattern of initial increase followed by a subsequent decrease during seed development, while the plant growth-inhibiting hormone ABA showed the opposite trend. The findings indicate that the alterations in nutrient composition, antioxidant enzyme activity, and endogenous hormone levels vary throughout the maturation process of N. incisum seeds. These observations hold relevance for the cultivation of N. incisum seeds.

Emerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents a unique ecological niche with diverse wildlife that harbours several human pathogens and numerous previously uncharacterized pathogens. In this study, we identified and characterized a novel arenavirus (namely, plateau pika virus, PPV) from plateau pikas ( Ochotona curzoniae ) on the Qinghai-Tibet Plateau by virome analysis. Isolated PPV strains could replicate in several mammalian cells. We further investigated PPV pathogenesis using animal models. PPV administered via an intraventricular route caused trembling and sudden death in IFNαβR -/- mice, and pathological inflammatory lesions in brain tissue were observed. According to a retrospective serological survey in the geographical region where PPV was isolated, PPV-specific IgG antibodies were detected in 8 (2.4%) of 335 outpatients with available sera. Phylogenetic analyses revealed that this virus was clearly separated from previously reported New and Old World mammarenaviruses. Under the co-speciation framework, the estimated divergence time of PPV was 77-88 million years ago (MYA), earlier than that of OW and NW mammarenaviruses (26-34 MYA).

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination (HR) deficient cancer cells and elicit anticancer effect through a mechanism of synthetic lethality. In this study, we designed, synthesized and pharmacologically evaluated a series of [1,2,4]triazolo[4,3-a]pyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds 17m, 19a, 19c, 19e, 19i and 19k not only displayed more potent inhibitory activities (IC 50 s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1 -/- , IC 50 s < 1.9 nM) and Capan-1 (BRCA2 -/- , IC 50 s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC 50 s < 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death globally. Oxidative stress affects various molecular mechanisms and is the main driving factor of COPD. Ally isothiocyanate (AITC) is an effective component of Semen Sinapis Albae, which has favorable effects for the treatment of COPD, but its mechanism has not been fully elucidated., Purpose: This study aimed to elucidate the antioxidant effect of AITC on COPD and its molecular mechanism, and preliminarily determine the role of AhR in the progression of COPD., Study Design: The COPD rat model was established by smoking combined with intratracheal instillation of lipopolysaccharide. Different doses of AITC, positive control drug acetylcysteine, AhR inhibitor alpha-naphthoflavone, and agonist beta-naphthoflavone were administered by gavage. Human bronchial epithelial cells induced by cigarette smoke extract (CSE) were used in an in vitro model to explore the molecular mechanisms of AITC., Methods: The effects of AITC on lung function and oxidative stress in rats were evaluated in vivo using the respiratory function test, white blood cell count, enzyme-linked immunosorbent assay, and histological staining. The changes in protein expression in the lung tissue were detected by immunohistochemistry and Western blotting. RT-PCR, western blotting, and immunofluorescence were used to explore the molecular mechanisms of AITC. Enzyme-linked immunosorbent assay, reactive oxygen species probing, and flow cytometry were used to determine the antioxidant effect of AITC., Results: AITC can improve the lung function of rats with COPD, restore lung tissue structure, improve oxidative stress, reduce inflammation, and inhibit lung cell apoptosis. AITC reversed the upregulation of AhR and CYP1A1 and the down-regulation of Nrf2 and NQO1 in the lung tissues of rats with COPD. CSE stimulation can increase the expressions of AhR and CYP1A1 and decrease the expressions of Nrf2 and NQO1 in 16HBE cells, leading to severe oxidative stress and inflammatory response and, ultimately, apoptosis. AITC inhibited AhR and CYP1A1 expressions, induced Nrf2 and NQO1 expressions, promoted Nrf2 nuclear translocation, and improved CSE-induced toxicological effects., Conclusion: AITC may improve lung oxidative stress by inhibiting the AhR / CYP1A1 and activating the Nrf2 / NQO1 pathways, thereby delaying the pathological progression of COPD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Pancreaticoduodenectomy combined with portal vein (PV) and/or superior mesenteric vein (SMV) resection in patients with pancreaticobiliary malignancy has become a common surgical procedure. There are various grafts currently used for PV and/or SMV reconstruction, but each of these grafts have certain limitations. Therefore, it is necessary to explore novel grafts that have an extensive resource pool, are low cost with good clinical application, and are without immune response rejection or additional damage to patients., Aim: To observe the anatomical and histological characteristics of the ligamentum teres hepatis (LTH) and evaluate PV/SMV reconstruction using an autologous LTH graft in pancreaticobiliary malignancy patients., Methods: In 107 patients, the post-dilated length and diameter in resected LTH specimens were measured. The general structure of the LTH specimens was observed by hematoxylin and eosin (HE) staining. Collagen fibers (CFs), elastic fibers (EFs), and smooth muscle (SM) were visualized by Verhoeff-Van Gieson staining, and the expression of CD34, factor VIII-related antigen (FVIIIAg), endothelial nitric oxide synthase (eNOS), and tissue type plasminogen activator (t-PA) were detected using immunohistochemistry in LTH and PV (control) endothelial cells. PV and/or SMV reconstruction using the autologous LTH was conducted in 26 patients with pancreaticobiliary malignancies, and the outcomes were retrospectively analyzed., Results: The post-dilated length of LTH was 9.67 ± 1.43 cm, and the diameter at a pressure of 30 cm H 2 O was 12.82 ± 1.32 mm at the cranial end and 7.06 ± 1.88 mm at the caudal end. Residual cavities with smooth tunica intima covered by endothelial cells were found in HE-stained LTH specimens. The relative amounts of EFs, CFs and SM in the LTH were similar to those in the PV [EF (%): 11.23 ± 3.40 vs 11.57 ± 2.80, P = 0.62; CF (%): 33.51 ± 7.71 vs 32.11 ± 4.82, P = 0.33; SM (%): 15.61 ± 5.26 vs 16.74 ± 4.83, P = 0.32]. CD34, FVIIIAg, eNOS, and t-PA were expressed in both LTH and PV endothelial cells. The PV and/or SMV reconstructions were successfully completed in all patients. The overall morbidity and mortality rates were 38.46% and 7.69%, respectively. There were no graft-related complications. The postoperative vein stenosis rates at 2 wk, 1 mo, 3 mo and 1 year were 7.69%, 11.54%, 15.38% and 19.23%, respectively. In all 5 patients affected, the degree of vascular stenosis was less than half of the reconstructed vein lumen diameter (mild stenosis), and the vessels remained patent., Conclusion: The anatomical and histological characteristics of LTH were similar to the PV and SMV. As such, the LTH can be used as an autologous graft for PV and/or SMV reconstruction in pancreaticobiliary malignancy patients who require PV and/or SMV resection., Competing Interests: Conflict-of-interest statement: The authors have no related conflicts of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To explore the pharmacological effects and molecular mechanism of quercetin 7-rhamnoside (Q7R) in the treatment of cholestatic hepatitis induced by alpha-naphthylisothiocyanate (ANIT). Methods: ANIT-induced cholestatic hepatitis rat model was used to investigate the hepatoprotective effects of three different doses of Q7R (1.25 mg/kg; 2.5 mg/kg; 5 mg/kg). Serum biochemical indices were detected using commercial kits. H&E and masson staining were used to observe hepatic tissue damage and collagen deposition in hepatocytes. The metabolism of bile acid-related substances was detected via HPLC-MS/MS by 5-(diisopropylamino) amylamine (DIAAA) derivative method. Hepatocyte injury, cholestasis, and inflammation were detected at the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, respectively. Results: Q7R can decrease the level of CYP7A1, and increase FXR, CYP27A1 so then improving abnormal bile acid secretion. Furthermore, Q7R can also ameliorating inflammation by reduce TNF-α, IL-1β, PTGS1, PTGS2, NCOA2, NF-κB level. Therefore, Q7R had an effective therapeutic effect on ANIT-induced cholestatic hepatitis, improving abnormal bile acid secretion, and inhibiting inflammatory responses. Conclusion: The results demonstrated that Q7R treat cholestatic hepatitis by regulating bile acid secretion and alleviating inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jin, Liu, Feng, Zhu, Feng, Cao and Yuan.)

This study was conducted to evaluate the efficacy and safety of Simotang Oral Liquid in the treatment of functional dyspepsia in adults. &quot;Simotang Oral Liquid&quot; &quot;Simotang&quot; &quot;Si Mo Tang&quot; &quot;Si Mo Tang Oral Liquid&quot; were used for retrieval of the relevant papers from CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, Springer Link, and Web of Science from database inception to June 2021. Randomized controlled trial(RCT) of Simotang Oral Liquid in the treatment of functional dyspepsia in adults was screened out for Meta-analysis which was conducted in RevMan 5.3. A total of 16 RCTs were included. Meta-analysis showed that compared with the control group, Simotang Oral Liquid increased the total response rate and lowered the traditional Chinese medicine syndrome scores, serum cholecystokinin(CCK), serum nitric oxide(NO), and incidence of adverse reactions. However, the serum substance P(SP) had no statistical difference between the two groups. Simotang Oral Liquid is effective and safe in the treatment of functional dyspepsia in adults. However, this study has evidence and limitations, so the conclusions need to be further verified by large sample and multicenter clinical studies.

Background and Study Aims: Glucocorticoid (GC) treatment for liver failure is controversial. This study sought to evaluate the efficacy and predictive factors of glucocorticoid therapy for hepatitis B virus-related acute-on-chronic liver failure (HBV- ACLF)., Patients and Methods: A total of 302 patients with HBV- ACLF were enrolled and categorized by treatment modality (GC vs. Control). Baseline characteristics, liver function, disease complications, and mortality were recorded. Univariate and multivariate analysis were used to identify predictive factors for HBV-ACLF-related mortality., Results: GC therapy significantly improved the 30- and 60-day mortality of HBV-ACLF patients (4.64% vs. 11.92%, P=0.022 and 16.56% vs. 25.83%, P=0.049 for the Control and GC groups, respectively) and GC was an independent prognostic factor for 30-day mortality (OR = 0.177, 95% CI 0.051-0.616, P = 0.007). However, enhanced survival was not associated with improved liver function. There were no significant differences in the incidence of complications (i.e., ascites, bacterial infection, encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding) between the GC and Control groups (P >0.05), except that fungal infection occurred with higher frequency in the GC group (P = 0.037). A significant improvement in the 30-day survival associated with GC therapy was observed among patients <40 years of age, a Model for End-stage Liver Disease (MELD) score of 25-35 or a CLIF- Consortium ACLF (CLIF-C ACLF) grade 0-1 (all P <0.05)., Conclusions: GC therapy improved the short-term (30- and 60- day) mortality of patients with HBV-ACLF. This treatment may be of particular benefit to patients who are <40 years of age, have a MELD score of 25-35, or have a CLIF-C ACLF grade of 0-1. (Acta gastroenterol. belg., 2022, 85, 593-600)., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

Context: Stroke is an acute cerebrovascular disease and a neurological disorder that occurs due to a cerebral arterial embolism and rupture. Acute stroke is often accompanied by dysphagia, which reduces patients' intake of food and nutrients, decreases their nutritional status, and affects their quality of life., Objective: The study intended to identify the demographic and clinical characteristics of stroke patients with dysphagia and to explore the relationship of those characteristics to nutritional status and prognosis., Methods: The research team retrospectively collected the clinical data of patients to compare the nutritional status and prognoses of patients with different demographic and clinical characteristics., Setting: The study took place in the Department of Neurology at the First People's Hospital of Shenyang in Shenyang, China., Participants: Participants were 789 stroke patients with dysphagia who had been admitted to the general ward of the neurology departments of hospitals of Grade 3 or higher in Northeast China between January 2019 and September 2020. Based on the results of the Nutrition Risk Screening (NRS-2002) and Subjective Global Assessment (SGA) scales at baseline, participants were enrolled in this study., Outcome Measures: The outcomes were the correlations between participants' demographic and clinical characteristics and their nutritional statuses and prognoses. The Modified Rankin Scale (mRS) was used to evaluate the prognosis of the patients at seven days and three months after participants' enrollment in the study. Using the SPSS 26.0, a t test, chi-square test, and F test were performed to analyze and verify the presence of fundamental differences in baseline characteristics between participants with good nutrition and those with poor nutrition. Also, a statistical correlation analysis was performed., Results: The study showed that participants with different nutritional levels had statistically significant differences in the presence or absence of infections and body temperature and scores on the Standardized Swallowing Assessment (SSA) and National Institutes of Health Stroke Scale (NIHSS), with all P < .001. At baseline seven days after enrollment, the prognoses of participants were significantly different for different previous histories of stroke (P < .001), family history of stroke (P = .005), presence or absence of infections (P < .001), body temperature (P < .001), and SSA (P < .001) and NIHSS (P < .001) scale scores. At three months after enrollment, the prognoses of participants were significantly different for previous history of stroke (P = .003), different body temperatures (P < .001), presence or absence of infections(P < .001), and SSA (P < .001) and NIHSS (P < .001) scale scores. Age, gender, family history of stroke, smoking, alcohol consumption, previous history of stroke, education level, SSA scale score, NIHSS scale score, body mass index (BMI), body temperature, and infection were adjusted in the model. Nutritional status as classified by NRS-2002 and SGA was significantly correlated with prognosis (P < .001). The prognosis of stroke patients with dysphagia was associated with nutritional status by unconditional logistic regression., Conclusion: The prognosis of stroke patients with dysphagia is related to their nutritional status. A better nutritional status indicates the better prognosis, and vice versa. In clinical treatment, attention should be paid to use of a nutritional intervention.

Objective: To explore the active components and epigenetic regulation mechanism underlying the anti-inflammatory effects of Lonicerae Japonicae Flos and Forsythiae Fructus herb-pair (LFP) in carbon tetrachloride (CCl 4 )-induced rat liver fibrosis. Methods: The main active ingredients and disease-related gene targets of LFP were determined using TCMSP and UniProt, and liver fibrosis disease targets were screened in the GeneCards database. A network was constructed with Cytoscape 3.8.0 and the STRING database, and potential protein functions were analyzed using bioinformatics analysis. Based on these analyses, we determined the main active ingredients of LFP and evaluated their effects in a CCl 4 -induced rat liver fibrosis model. Serum biochemical indices were measured using commercial kits, hepatocyte tissue damage and collagen deposition were evaluated by histopathological studies, and myofibroblast activation and inflammation were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. High-performance liquid chromatography-mass spectrometry was performed to determine the levels of homocysteine, reduced glutathione, and oxidized glutathione, which are involved in inflammation and oxidative stress. Results: The main active components of LFP were quercetin, kaempferol, and luteolin, and its main targets were α-smooth muscle actin, cyclooxygenase-2, formyl-peptide receptor-2, prostaglandin-endoperoxide synthase 1, nuclear receptor coactivator-2, interleukinβ, tumor necrosis factor α, CXC motif chemokine ligand 14, and transforming growth factor β1. A combination of quercetin, kaempferol, and luteolin alleviated the symptoms of liver fibrosis. Conclusion: The results of this study support the role of LFP in the treatment of liver fibrosis, and reveal that LFP reduces collagen formation, inflammation, and oxidative stress. This study suggests a potential mechanism of action of LFP in the treatment of liver fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Jin, Feng, Feng, Zhu, Nan and Yuan.)

Rhizosphere soil microbial community and its diversity are important for the structure and functions of medicinal plant ecosystem. In this study, based on high-throughput sequencing, rhizosphere soil microbial diversity, and yield and quality of rhizome and root of Notopterygium incisum cultivated alone(control, CK) and intercropped with Vicia faba(QH) were analyzed, which is expected to lay a basis for optimization of the cultivation mode and ecological production of N. incisum. RESULTS:: showed that the rhizosphere soil bacteria of N. incisum were dominated by Proteobacteria and Bacteroides, with the relative abundance of 50.38%-51.95% and 16.36%-17.02%, respectively. Soil bacterial community at the phylum level was not significantly different between CK and QH. At the genus level, the relative abundance of MND1(3.54%), Spinstomonas(3.50%), Nitrospira(1.53%), and Rhizobacter(1.05%) was significantly higher and that of Gemmatimonas, Candidatus＿Solibacter, and Bryophytes was lower in QH treatment than in the CK. The plant height, leaf length, leaf width, and petiole length of N. incisum in QH treatment was significantly increased and the underground biomass rose by 71.43% compared with those in the CK. Thus, intercropping with V. faba promoted the aboveground growth of N. incisum and improved the yield of root and rhizome. Moreover, the content of notopterol and isoimperatorin increased by 37.96% and 4.09% in QH treatment, respectively, indicating that the intercropping with V. faba boosted the accumulation of secondary metabolites in N. incisum. Pearson's correlation analysis showed that the soil bacterial community was mainly influenced by the soil factors including the content of soil available nutrients, soil organic matter, pH value, and soil water. The influence was in the order: total potassium&gt;total nitrogen&gt;pH&gt;organic matter&gt;available potassium&gt;soil water content&gt;available nitrogen&gt;available phosphorus. In conclusion, the intercropping with V. faba altered soil microenvironment and also increased the yield and accumulation of secondary metabolites of N. incisum, which is a promising ecological planting model for N. incisum.

Background: Mechanical loading has been widely considered to be essential for growth plate to maintain metabolism and development. Cyclic mechanical strain has been demonstrated to induce autophagy, whereas the relationship between cyclic tensile strain (CTS) and autophagy in growth plate chondrocytes (GPCs) is not clear. The objective of this study was to investigate whether CTS can regulate autophagy in GPCs in vitro and explore the potential mechanisms of this regulation., Methods: The 2-week-old Sprague-Dawley rat GPCs were subjected to CTS of varying magnitude and duration at a frequency of 2.0 Hz. The mRNA levels of autophagy-related genes were measured by RT-qPCR. The autophagy in GPCs was verified by transmission electron microscopy (TME), immunofluorescence and Western blotting. The fluorescence-activated cell sorting (FACS) was employed to detect the percentage of apoptotic and necrotic cells., Results: In GPCs, CTS significantly increased the mRNA and protein levels of autophagy-related genes, such as LC3, ULK1, ATG5 and BECN1 in a magnitude- and time-dependent manner. There was no significant difference in the proportion of apoptotic and necrotic cells between control group and CTS group. The autophagy inhibitors, 3-methyladenine (3MA) and chloroquine (CQ) reversed the CTS-induced autophagy via promoting the formation of autophagosomes. Cytochalasin D (cytoD), an inhibitor of G-actin polymerization into F-actin, could effectively block the CTS-induced autophagy in GPCs., Conclusion: Cyclic mechanical strain with high-tensile triggers autophagy in GPCs, which can be suppressed by 3MA and CQ, and cytoskeletal F-actin microfilaments organization plays a key role in chondrocytes' response to mechanical loading., (© 2022. The Author(s).)

Anterior cruciate ligament (ACL) rupture is a common musculoskeletal injury, most frequently affecting young and physically active patients. Platelet-rich plasma (PRP) has been widely used in ACL reconstruction to augment the graft healing. However, high-level studies addressing its clinical efficacy could not reach a consensus. In this study, we assess the efficacy of PRP on pain relief, functional improvement along with radiological changes in patients who underwent ACL reconstruction. We performed comprehensive literature search and included 17 RCTs containing 970 participants who underwent ACL reconstruction. The combined data showed significant difference between PRP and control with regard to VAS score (MD: -1.12, 95% CI -1.92, -0.31; P = .007), subjective IKDC score (MD: 6.08, 95% CI 4.39, 7.77; P < .00001) and Lysholm score (MD: 8.49, 95% CI 1.63, 15.36; P = .02) by postoperative 6 months, but only pain reduction was deemed clinically important. At the end of one year's follow-up, no clinically meaningful improvement in VAS (MD: -0.47, P = .04), subjective IKDC score (MD: 3.99, P = .03), Lysholm score (MD: 2.30, P = .32), objective IKDC score (RR: 1.03, P = .09) and knee joint laxity (MD: 0.17, P = .28) was seen. In terms of radiological findings, about one-third of the studies favored PRP to facilitate the graft healing, improve the harvest site morbidity and prevent tunnel widening. In summary, moderate quality of evidence suggested that PRP could provide short-term but not long-term clinically important pain reduction.

Human immunodeficiency virus (HIV) infection and highly active antiretroviral therapy use are associated with the disruption of lipid and glucose metabolism. Herein, a sensitive and robust high-performance liquid chromatography-tandem mass spectrometry method for the quantitation of lysophosphatidylcholines (LPCs) and acylcarnitines (ACs) in human blood serum was developed and validated to investigate them as markers of metabolic disorders in HIV-infected patients. Under optimal extraction and detection conditions, the lower limits of quantification reached 5 ng/mL (LPCs) and 0.1 ng/mL (ACs), and precision and accuracy for both intra- and inter-day analyses were generally below 15%. Serum samples were stable for at least six months when stored at - 80 °C and for at least 12 h when stored at 4 °C or 25 °C. We investigated inter-group differences and associations between the biomarkers and observed a particular volatilitytrend of LPCs and ACs for HIV-infected patients with metabolic disorders. Thus, the developed method can be used for the rapid and sensitive quantitation of LPCs and ACs in vivo to further appraise the process of HIV infection, evaluate interveningmeasures, conduct mechanistic investigations, and further study the utility of LPCs and ACs as biomarkers of HIV infection coupled with metabolic disorders., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

A new alkylresorcinol, myrothecol A ( 1 ), along with two known ones ( 2 and 3 ), were isolated from a fungal strain Myrothecium sp. GY170016. Their structures were elucidated by extensive spectroscopic analysis. The absolute configuration of 1 was determined by electronic circular dichroism experiment. This is the first case of the presence of alkylresorcinols in genus Myrothecium . All the isolates were evaluated for their cytotoxic activities against human cancer cell line MCF-7 with IC 50 values of 16.7, 13.2, 21.3  μ M, respectively.

Background and Aims: Allyl isothiocyanate(AITC) has been shown to play an important role in the improved symptoms of chronic obstructive pulmonary disease(COPD) and the inhibition of inflammation, but the role in COPD lipid metabolism disorder and the molecular mechanism remains unclear. We aimed to explore whether and how AITC affects COPD by regulating lipid metabolism and inflammatory response., Methods: The COPD rat model was established by cigarette smoke exposure. Cigarette smoke extract stimulated 16HBE cells to induce a cell model. The effect of AITC treatment was detected by lung function test, H&E staining, Oil red O staining, immunohistochemistry, ELISA, CCK-8, HPLC, fluorescence efflux test, siRNA, RT-PCR, and Western blotting. Biological analysis was performed to analyze the results. Graphpad Prism 8.0 software was used for statistical analysis., Results: AITC can improve lung function and pathological injury in COPD rats. The levels of IL-1 β and TNF- α in the AITC treatment group were significantly lower than those in the model group(P < 0.05), and the lipid metabolism was also improved (P < 0.05). AITC reverses CSE-induced down-regulation of LXR α, ABCA1, and ABCG1 expression and function in a time-and concentration-dependent manner (P < 0.05). AITC regulates the cholesterol metabolism disorder induced by CSE in NR8383 cells and attenuates macrophage inflammation (P < 0.05). In addition, after silencing LXR α with siRNA, the effect of AITC was also inhibited., Conclusion: These results suggest that AITC improves COPD by promoting RCT process and reducing inflammatory response via activating LXR pathways., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1β-induced chondrocyte inflammation response. Moreover, PA reduced IL-1β-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1β-induced chondrocytes could be reversed when integrin αVβ3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVβ3. Thus, PA or integrin αVβ3 might be a promising agent or molecular target for the treatment of OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Yu, Liang, Cheng, Wang, He, Lv, Wan, Mo, Zhu and Chen.)

Background: The current study analyzed resected stage I-IIIA pulmonary lymphoepithelioma-like carcinoma (LELC) cases to define the clinical characteristics, prognosis and long-term outcomes of resected LELC, with the purpose of guiding clinical management for this rare tumor. Methods: Resected stage I-IIIA LELC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cases from our center were enrolled. Propensity score matching (PSM) was applied to minimize the selection bias. Overall survival (OS) and disease-free survival (DFS) were compared between groups. Multivariate analyses were performed to identify the prognostic factors, and a nomogram was developed. Results: A total of 159 LELCs, 2,757 ADCs, and 1,331 SCCs were included. LELC, dominated among younger patients and non-smokers. LELC was a poorly differentiated disease that lacked driver gene mutations and was positive for immunohistochemistry indicators of squamous cell lineage. Survival analyses revealed that OS was significantly better for LELC than for other common non-small cell lung cancers (NSCLCs) both before PSM (all P < 0.001) and after PSM (all P < 0.05). Further analyses revealed that early pathological node stage and preoperative albumin level ≥35 were identified as independent prognostic factors favoring OS and DFS. Conclusions: LELC, dominated among younger and non-smoking populations, lacked driver gene mutations and was positive for immunohistochemistry indicators of squamous cell lineage. The survival outcome of LELC was better than other common NSCLCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiang, Feng, Zhu, Guo, Tan, Jiang, Dou and Liu.)

Objective: To detect the ABO / RhD blood type of infants younger than 6 months in different gestational age and month old with automatic microcolumn glass sphere and tube method, and compare the result of the two methods., Methods: The data of 896 samples of infants younger than 6 months from January 2018 to February 2019 was collected. The two methods were used to detect ABO/RhD blood type in all samples and compare the detection rate of ABO/RhD antigen and ABO reverse typing and agglutination intensity of the two methods., Results: Three hundred and eight cases of type A (34.4%), 281 cases of type B (31.4%), 210 cases of type O (23.4%), 97 cases of type AB (10.8%), and 896 positive cases of RhD blood type were detected out by two methods. There were no significant differences of ABO/RhD antigen agglutination intensity between two methods (P > 0.05). Except for type AB, the detection rate of ABO reverse typing in infants with type B was significantly higher than that with type A and type O (P < 0.05). The agglutination intensity of type A reverse cell was higher than type B reverse cell (P < 0.05). The fully automatic microcolumn glass sphere method exhibited higher detection rate of ABO reverse typing in the samples of type A and type O group and agglutination intensity of ABO reverse typing in all types as compared with the tube method (P < 0.05). The detection rate and agglutination intensity of ABO reverse typing in term group were significantly higher than those in preterm group (P < 0.05). The fully automatic microcolumn glass sphere method exhibited higher detection rate of ABO reverse typing and agglutination intensity compared with the tube method between two groups (P < 0.05). The detection rate and agglutination intensity of ABO reverse typing in group IV (4-6 months old) were significantly higher than those in groups I, II and III (young than 3 months old) (P < 0.05). The fully automatic microcolumn glass sphere method exhibited higher detection rate of ABO reverse typing in I, II, III groups and agglutination intensity of ABO reverse typing in the 4 groups compared with the tube method (P < 0.05)., Conclusion: ABO / RhD blood group antigen can be accurated detected in majority of infants, but the detection rate of ABO antibody is related to gestational age and month age of infants. The detection rate and agglutination intensity of the fully automatic microcolumn glass sphere method in ABO reverse typing are higher than those of the tube method, especially for premature infants and children within 3 months old.

Excessive biomechanical loading is considered an important cause of osteoarthritis. Although the mechanical responses of chondrocytes and osteoblasts have been investigated, their communication during mechanical loading and the underlying molecular mechanisms are not yet fully known. The present study investigated the effects of excessive mechanically stretched osteoblasts on the metabolism and apoptosis of chondrocytes, and also assessed the involvement of the Wnt/β‑catenin signaling pathway. In the present study, rat chondrocytes and osteoblasts were subjected to mechanical tensile strain, and an indirect chondrocyte‑osteoblast co‑culture model was established. Reverse transcription‑quantitative PCR and western blotting were performed to determine the expression levels of genes and proteins of interest. An ELISA was performed to investigate the levels of cytokines, including matrix metalloproteinase (MMP) 13, MMP 3, interleukin‑6 (IL‑6) and prostaglandin E2 (PG E2), released from osteoblasts. Flow cytometry was performed to detect the apoptosis of chondrocytes exposed to stretched osteoblast conditioned culture medium. The levels of MMP 13, IL‑6 and PG E2 increased significantly in the supernatants of stretched osteoblasts compared with the un‑stretched group. By contrast, the mRNA expression levels of Collagen 1a and alkaline phosphatase were significantly decreased in osteoblasts subjected to mechanical stretch compared with the un‑stretched group. The mRNA expression level of Collagen 2a was significantly decreased, whereas the expression levels of MMP 13 and a disintegrin and metalloproteinase with thrombospondin‑like motifs 5 were significantly increased in chondrocytes subjected to mechanical stretch compared with the un‑stretched group. In the co‑culture model, the results indicated that excessive mechanically stretched osteoblasts induced the catabolism and apoptosis of chondrocytes, which was partly inhibited by Wnt inhibitor XAV‑939. The results of the present study demonstrated that excessive mechanical stretch led to chondrocyte degradation and inhibited osteoblast osteogenic differentiation; furthermore, excessive mechanically stretched osteoblasts induced the catabolism and apoptosis of chondrocytes via the Wnt/β‑catenin signaling pathway.

The species-habitat association analysis facilitates a better understanding of species coexis-tence and community assembly. Here, all trees in a 25-hm 2 broadleaved deciduous forest plot in the Qinling Mountains of North-central China were classified into three life stages ( i.e ., seedling, sapling, and adult). The Torus-translation test was used to examine the species-habitat association. The results showed that the association of species with habitats varied across different species. Most species were significantly associated with high slopes, 95.7% of which showed negative association. 89.5% and 90.9% of tree species were negatively associated with low slopes and ridges, respectively. Most species had positive association with high valley, with only one negative association (0.03%). There were 80, 44 and 23 significant associations with habitats at seedling, sapling and adult stages, respectively, indicating that a greater dependence of seedlings on habitat. 38 species at seedling stage and 25 species at the sapling stage were associated with at least one habitat type, while only 17 species at the adult stage were significantly associated. The effects of habitat on species varied across life stages, showing a weaker species-habitat association at the later stage. Due to the specific environmental demands, most species showed different habitat preferences across life stages.

Ferroptosis is a type of oxidative stress-dependent regulated necrosis characterized by excessive lipid peroxide accumulation. This novel cell death modality has been implicated in preventing cancer progression. Cancer cells tend to modulate their redox state to prevent excessive peroxidation, eventually facilitating tumor growth. System Xc - (a cystine/glutamate antiporter system) is a promising target in cancer cells for ferroptosis induction. The overexpression of system Xc - , especially its core subunit xCT, has been reported in several tumors, and these high expression levels were closely related to cancer cell proliferation, invasion, metastasis and the tumor microenvironment. xCT might serve as a novel biomarker, and its upregulation almost always indicates drug tolerance and poor survival. Therefore, system Xc - inhibition may enhance chemotherapy sensitivity and optimize patient prognosis. Here, we elaborate on the mediation of ferroptosis by suppressing system Xc - and the relevant underlying molecular mechanism in cancer cells. The spotlight on this approach to cancer treatment is creating a new horizon and pointing to future opportunities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Context: Small-for-gestational-age (SGA) is an indicator of poor fetal growth "programming" an elevated risk of type 2 diabetes in adulthood. Little is known about early-life endocrine characteristics in SGA subtypes. Stunting (short) and wasting (skinny) are considered distinct SGA phenotypes in neonatal prognosis., Objectives: This work aimed to assess whether SGA infants with stunting or wasting have similar alterations in neonatal endocrine metabolic health biomarkers., Methods: This was a nested case-control study based on the 3D (Design, Develop, and Discover) birth cohort in Canada. The study subjects were 146 SGA (birth weight < 10th percentile) and 155 optimal-for-gestational age (OGA, 25th-75th percentiles) infants. Stunting was defined as birth length less than the 10th percentile, and wasting as body mass index less than the 10th percentile for sex and gestational age, respectively. Main outcome measures included cord plasma concentrations of insulin-like growth factor I (IGF-I), proinsulin, leptin, high-molecular-weight (HMW) adiponectin, and ghrelin., Results: Comparing to OGA infants adjusted for maternal and neonatal characteristics, SGA infants with either stunting only or wasting only had lower cord plasma IGF-I and leptin concentrations. HMW adiponectin concentrations were lower in SGA infants with wasting only (P = .004), but similar in SGA infants with stunting only (P = .816). Only SGA infants with both stunting and wasting had substantially lower proinsulin (P < .001) and higher ghrelin concentrations (P < .001) than OGA infants., Conclusion: This study is the first to demonstrate that SGA infants with wasting only are characterized by low HMW adiponectin concentrations, whereas those with stunting only are not. SGA with both stunting and wasting are characterized by low proinsulin and high ghrelin concentrations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To evaluate the economics of Suhuang Zhike Capsules in the treatment of acute exacerbation of chronic obstructive pulmonary disease(AECOPD) for inpatients. Based on the published clinical research data, cost-utility analysis was used in this study to evaluate the pharmacoeconomics of Suhuang Zhike Capsules in treatment of AECOPD inpatients from the perspective of medical insu-rance. The test group was treated with Suhuang Zhike Capsules combined with conventional Western medicine, and the control group was treated with conventional Western medicine alone. Treeage software was used to construct a pharmacoeconomic model and perform simulation analysis. The results showed that the cost and output of Suhuang Zhike Capsules combined with the conventional Western medicine were 60 010.18 yuan and 1.92 quality adjusted life year(QALYs), respectively in the simulated 3 years of disease treatment. The cost and output of the conventional Western medicine were 96 730.60 yuan and 1.90 QALYs respectively. Suhuang Zhike Capsules combined with conventional Western medicine required lower cost but achieved higher output, showing cost-utility advantages, so this drug combination was a plan with pharmacoeconomic advantages. The sensitivity analysis results showed that the conclusion was relatively stable. Based on the above results, it is believed that as compared with the conventional Western medicine, Suhuang Zhike Capsules combined with conventional Western medicine have lower cost and higher output for the treatment of AECOPD inpatients, and it is a treatment plan with pharmacoeconomic advantages.

The aim of the research was to evaluate the efficacy and safety associated with Shexiang Tongxin Dropping Pills combined with conventional therapy for patients with coronary heart disease(CHD). We searched 8 electronic databases up to November 2020, including PubMed, Cochrane Library, EMbase, Web of Science, CNKI, Wanfang, VIP and SinoMed. Eligible studies were clinical trials of Shexiang Tongxin Dropping Pills combined with conventional therapy used in the treatment of coronary heart disease(CHD). The Meta-analysis was performed using STATA 15 software. A total of 21 RCTs(n=2 186) were shortlisted for the Meta-analysis. The results of efficacy evaluation showed that the total effective rate of Shexiang Tongxin Dropping Pills combined with conventional therapy was higher than that of conventional therapy of coronary heart disease(RR=1.20, 95%CI[1.15, 1.26], Z=8.63, P&lt;0.001). Furthermore, Shexiang Tongxin Dripping Pills combined with conventional therapy had better effect on electrocardiogram efficacy(RR=1.24, 95%CI[1.16, 1.34], Z=5.98, P&lt;0.001) and the number of angina attacks(SMD=-2.30, 95%CI[-3.47,-1.14], Z=3.88, P&lt;0.001), the duration of angina attack(SMD=-2.31, 95%CI[-3.07,-1.55], Z=5.97, P&lt;0.001), with lower levels of LDL-C(SMD=-0.73, 95%CI[-1.32,-0.14], Z=2.42, P=0.016), TC(SMD=-1.16, 95%CI[-1.35,-0.96], Z=11.56, P&lt;0.001) and TG(SMD=-0.87, 95%CI[-1.06,-0.68], Z=8.97, P&lt;0.001), and higher levels of HDL-C(SMD=0.87, 95%CI[0.02, 1.71], Z=2.00, P=0.045). The results of safety evaluation showed that the incidence of adverse reactions of Shexiang Tongxin Dropping Pills combined with conventional therapy was lower than that of conventional therapy of coronary heart disease(RR=0.45, 95%CI[0.22, 0.91], Z=2.23, P=0.026). There were significant differences in the above outcome indexes between the two groups. After the Harbord method test, the total effective rate outcome index has publication bias, but the sensitivity analysis of the cut-and-fill method suggested that the result was stable. In general, limited by the quantity and quality of included literature, more high-quality studies are needed to further verify the conclusions of this study.

This research was to evaluate the economics of Shexiang Tongxin Dropping Pills combined with conventional therapy for patients with coronary heart disease(CHD) in Chinese medical environment. From the perspective of medical insurance, a Markov model was established in this study based on the results of Meta-analysis comparing the effectiveness and safety of Shexiang Tongxin Dripping Pills combined with conventional treatment and conventional treatment alone. The experimental group was treated with She-xiang Tongxin Dropping Pills combined with conventional Western medicine treatment, while the control group was treated with conventional Western medicine treatment alone. The cost-utility analysis and sensitivity analysis were performed for the two regimens using Treeage pro. After 30 cycles of model simulation, according to the results of Markov model, the total cost and health output were CNY 237 795.73 and 16.36 QALYs(the quality adjusted life years, QALYs), respectively for Shexiang Tongxin Dropping Pills combined with conventional Western medicine treatment, CNY 247 396.55 and 16.36 QALYs respectively for the conventional Western medicine treatment alone. Compared with the conventional treatment alone, the Shexiang Tongxin Dropping Pills combined with conventional treatment had lower long-term cost and higher health output, with advantages of cost-utility and pharmacoeconomic advantages. The sensitivity analysis results showed that the conclusion was relatively stable. Based on the above results, it is considered that compared with the conventional Western medicine alone, Shexiang Tongxin Dropping Pill combined with conventional Western medicine is a treatment regimen with pharmacoeconomic advantages for the treatment of CHD.

Epidermal growth factor-like domain multiple 6 (EGFL6) is implicated in tumor growth, metastasis and angiogenesis, and its ectopic alteration has been detected in aggressive malignancies. However, the pathophysiologic roles and molecular mechanisms of EGFL6 in gastric cancer (GC) remain to be elucidated. In this study, we investigated EGFL6 expression in GC cell lines and tissues using western blotting and immunohistochemistry. We found that EGFL6 was elevated expression in GC cell lines and tissues. The high expression of EGFL6 significantly was correlated with histological grade, depth of invasion, lymph node involvement, distant metastasis and TNM stage in GC and predicted poorer prognosis, and it could act an independent prognostic factor for GC patients. EGFL6 enhanced the proliferation, migration and invasion of GC cells. In addition, we identified the possible molecular mechanisms of EGFL6-involved epithelial-mesenchymal transition (EMT). EGFL6 regulated EMT process and induced metastasis partly through FAK/PI3K/AKT/mTOR, Notch and MAPK signaling pathways. In conclusion, EGFL6 confers an oncogenic function in GC progression and may be proposed as a potential therapeutic target for GC.

Four new monoterpenoid indole alkaloids, bousmekines A-D (1-4), and one new pyranopyridine alkaloid, bousmekine E (5), were isolated from the twigs and leaves of Bousigonia angustifolia and Bousigonia mekongensis. Their structures including absolute configurations were elucidated by a combination of MS, NMR, ECD calculation, and single-crystal X-ray diffraction analysis. Compound 2 was an eburnea-type MIAs characterized by a rare chlorine atom while 5 possessed a novel pyranopyridine moiety. Their cytotoxicities against several human cancer cell lines were evaluated and compound 1 exhibited significant cytotoxicity with IC 50 values of 0.8-7.4 μM.

N6-methyladenosine (m 6 A) RNA methylation is profoundly involved in epigenetic regulation, especially for carcinogenesis and tumor progression. Mounting evidence suggests that methyltransferase METTL3 regulates malignant behaviors of gastric cancer (GC). However, the clinical significance and biological implication of SPHK2 and its related m 6 A modification in GC remain unclear. In this study, quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were utilized to detect the expression profiles and prognostic significance of SPHK2 in GC. Here, we showed that increased SPHK2 was signified a poor prognosis of GC patients. Phosphorylation and ubiquitination assays were used to investigate the possible mechanisms of SPHK2-mediated KLF2 expression. SPHK2 can promote the phosphorylation of KLF2, which triggers the ubiquitination and degradation of KLF2 protein in GC. Methylated RNA immunoprecipitation (MeRIP) was performed to uncover the m 6 A modification of SPHK2 mRNA. METTL3 promotes translation of SPHK2 mRNA via an m 6 A-YTHDF1-dependent manner. Functionally, SPHK2 facilitates GC cell proliferation, migration and invasion by inhibiting KLF2 expression. SPHK2/KLF2 regulates the cell proliferation, migration, and invasion induced by METTL3 in GC. Overall, our findings reveal that METTL3-mediated m 6 A modification of SPHK2 contributes to GC progression, which extends the understanding of the importance m 6 A methylation in GC and represents a potential target for GC therapy.

BACKGROUND This network pharmacology study aimed to identify the active compounds and molecular mechanisms involved in the effects of Hypericum japonicum on cholestatic hepatitis. We validated the findings in an alpha-naphthylisothiocyanate (ANIT) rat model of hepatotoxicity. MATERIAL AND METHODS The chemical constituents and targets of H. japonicum and target genes previously associated with cholestatic hepatitis were retrieved from public databases. A network was constructed using Cytoscape 3.7.2 software and the STRING database and potential protein functions were analyzed based on the public platform of bioinformatics. ANIT was used to induce cholestatic hepatitis in a rat model using 36 Sprague-Dawley rats, and this model was used to investigate intervention with 3 doses of quercetin (low-dose, 50 mg/kg; medium-dose, 100 mg/kg; and high-dose, 200 mg/kg), the main active component of H. japonicum. Levels of serum biochemical indexes were measured by commercial kits, and the messenger RNA (mRNA) levels of markers of liver and mitochondrial function and oxidative stress were detected by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS The main active ingredients of H. japonicum were quercetin, kaempferol, and tetramethoxyluteolin, and their key targets included prostaglandin G/H synthase 2 (PTGS2), B-cell lymphoma-2 (BCL2), cholesterol 7-alpha hydroxylase (CYP7A1), and farnesoid X receptor (FXR). Quercetin intervention promoted recovery from cholestatic hepatitis. CONCLUSIONS The findings from this research provide support for future research on the roles of quercetin, kaempferol, and tetramethoxyluteolin in human liver disease and the roles of the PTGS2, BCL2, CYP7A1, and FXR genes in cholestatic hepatitis.

Fourteen undescribed monoterpenoid indole alkaloids, voacafrines A-N, along with 7 known monoterpenoid indole alkaloids were isolated from the seeds of Voacanga africana Stapf. Among them, voacafrines A-G were aspidosperma-aspidosperma type bisindole alkaloids, while voacafrines H-N were aspidosperma-type monomers. Their structures and absolute configurations were elucidated by a combination of NMR, MS, and ECD analyses. Voacafrines A-C were characterized by an acetonyl moiety at C-5', while voacafrine H possessed a methoxymethyl moiety at C-14 within aspidosperma-type alkaloids. The acetylcholinesterase (AChE) inhibitory activity and cytotoxicity of voacafrines A-N were evaluated. Voacafrines A-C and E-G were bisindole alkaloids that exhibited AChE inhibitory activity with IC 50 values of 4.97-33.28 μM, while voacafrines I and J were monomers that showed cytotoxicity against several human cancer cell lines with IC 50 values of 4.45-7.49 μM., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sono-photodynamic therapy (SPDT) activates the same photo-/sonosensitizer and exerts more marked antitumor effects than sonodynamic therapy or photodynamic therapy. We aimed to explore the utilization of curcumin (CUR)-loaded poly(L-lactide-co-glycolide) microbubble (MB)-mediated SPDT (CUR-PLGA-MB-SPDT) in HepG2 liver cancer cells. The cytotoxicity and intracellular accumulation of CUR were determined. We used 40 µM CUR as the photo-/sonosensitizer for 3 h. In a comparison of CUR-SDT or CUR-PDT, HepG2 cell viability decreased and apoptotic rate increased in CUR-SPDT. The CUR-PLGA MBs had round spheres with smooth surfaces and an average size of 3.7 µm. In CUR-PLGA MBs, drug entrapment efficiency and drug-loading capacity were 74.29 ± 2.60% and 17.14 ± 0.60%, respectively. CUR-loaded PLGA MBs (CUR-PLGA MBs) had good biocompatibility with normal L02 cells and were almost non-cytotoxic to HepG2 cells. Among CUR-SDT, CUR-PDT, CUR-SPDT or CUR-PLGA-MB-SDT, the cell CUR-PLGA-MB-SPDT had the lowest viability. Transmission electron microscopy revealed pyroptosis and apoptosis in the CUR-PLGA-MB-SPDT group; the potential mechanism was related to the mitochondrial membrane potential loss and increased production of intracellular reactive oxygen species. These findings suggested that CUR-PLGA-MB-SPDT may be a promising treatment for liver cancer., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

To clarify the difference of soil moisture characteristics between mixed broad leaf-conifer forest soil and artificial cultivation of Notopterygium incisum, the HYPROP system and the dew point potential meter were used to determine soil water retention curves(SWRC) for samples of two horizons(i.e. 2-7 cm, 10-15 cm). The basic physical and chemical properties of soil and its water characteristic parameters were also determined. The result showed as fllows:①The bulk density of mixed coniferous-broad leaf forest soil was between 0.33 and 0.52 g·cm~(-3), significantly lower than the corresponding value of field soil(1.01-1.18 g·cm~(-3))(P&lt;0.05), While the organic matter content was significantly higher than the corresponding value of field soil(P&lt;0.05). ②The saturated water content(θ&#95;s), field water holding capacity(θ&#95;(FC)) and Water that can be effectively utilized by plants(θ&#95;(PAC)) of mixed coniferous-broadleaved forest soil were significantly higher than the corresponding value of field soil(P&lt;0.05), while the retained water content(θ&#95;r) value that cannot be effectively utilized by plants was significantly lower than that of field soil(P&lt;0.05). ③The values of structural porosity(0.13-0.24 cm~3·cm~(-3)) and Matrix porosity(0.34-0.44 cm~3·cm~(-3)) of mixed coniferous-broadleaved forest soil were higher than the corresponding values of field soil. Therefore, with low bulk density and high content of organic matter, mixed coniferous-broadleaved forest soil can store more water in soil in the form of effective water to meet the needs of plants for water, thus possibly forming high quality medicinal materials of Notopterygii Rhizoma et Radix. In conclusion, the results of this study can provide theoretical basis guidance for soil structure improvement and water management to form high quality medicinal materials in the artificial cultivation of N. incisum.

Background: Emerging observational studies suggest an association between metabolic syndrome (MetS) and osteoarthritis (OA). This meta-analysis was conducted to examine whether or not there is a bidirectional relationship between MetS and OA., Methods: The PubMed and Embase databases were searched from their inception to October 2019. We selected studies according to predefined criteria. Random effects were selected to calculate two sets of pooled risk estimates: MetS predicting OA and OA predicting MetS., Results: A total of seven cross-sectional studies and four cohort studies met the criteria for MetS predicting the onset of OA. Another six cross-sectional studies and one cohort study met the criteria for OA predicting the onset of MetS. The pooled odds risk (OR) for OA incidences associated with baseline MetS was 1.45 (95% CI 1.27-1.66). The OR for MetS incidences associated with baseline OA was 1.90 (95% CI 1.11-3.27). In an overall analysis, we found that MetS was associated with prevalent OA in both cross-sectional studies (OR = 1.32, 95% CI 1.21-1.44) and cohort studies (OR = 1.76, 95% CI 1.29-2.42). No indication of heterogeneity was found in the cross-sectional studies (p = 0.395, I 2  = 4.8%), whereas substantial heterogeneity was detected in the cohort studies (p = 0.000, I 2  = 79.3%)., Conclusion: Meta-analysis indicated a bidirectional association between MetS and OA. We advise that patients with MetS should monitor their OA status early and carefully, and vice versa., Competing Interests: Competing interestsAll of the authors have no relevant conflicts of interest., (© The Author(s) 2020.)