Publications by authors named "Hongxia Zhu"

109 Publications

XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer.

Signal Transduct Target Ther 2021 Oct 20;6(1):357. Epub 2021 Oct 20.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.

Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206 TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking "don't eat me" recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.
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http://dx.doi.org/10.1038/s41392-021-00761-7DOI Listing
October 2021

Role of molecular size of volatile organic compounds on their adsorption by KOH-activated micro-mesoporous carbon.

J Hazard Mater 2021 Sep 29;424(Pt B):127355. Epub 2021 Sep 29.

Department of Environmental Science, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou 310058, China; Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 311200, China. Electronic address:

KOH-activated carbon (KAC) with high surface area and abundant micropores are widely used in adsorbing volatile organic compounds (VOCs). Kinetic diameters (σ) of VOCs are an important factor controlling diffusion of VOCs into pores of adsorbent. Yet the influence of kinetic diameters of VOCs on their adsorption by KAC remains unclear. Here, we investigated the dynamic adsorption of VOCs with various kinetic diameters on a prepared KAC with high surface area of 3100 m/g, pore volume of 2.08 cm/g and average pore width (D) of 2.68 nm. Adsorption affinity was negatively correlated with size difference (D-σ), indicating that pore width of adsorbent should close to σ to obtain a strong interaction between VOCs and adsorbents. Amounts adsorbed were positively correlated with σ at low relative pressures (p/p < 0.01), and negatively correlated with σ at high relative pressures (p/p > 0.044). The above results suggest that larger molecules with higher affinities are preferentially adsorbed at low relative pressures, amounts adsorbed of smaller molecules are larger than that of bigger molecules at high relative pressures. This study provided new insights into adsorption mechanisms mediated by σ and the development of next generation adsorbents for efficient removal of VOCs.
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http://dx.doi.org/10.1016/j.jhazmat.2021.127355DOI Listing
September 2021

The effect of training orthopedic nurse specialists in Jiangsu Province of China.

Ann Palliat Med 2021 Sep;10(9):9488-9496

Department of Orthopedic, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: The training of orthopedic nurse specialists is gradually increasing in China, but the effect of the training, namely the specialized nursing work carried out by them upon returning to work after training, is unknown. This study aimed to further our understanding of the effect of training orthopedic nurse specialists and provide a basis for improving the training program.

Methods: A total of 201 clinical nurse specialists who graduated from the training base of orthopedic nurse specialists in the Jiangsu Province were interviewed via a self-made questionnaire.

Results: All orthopedic nurse specialists completed a series of specialized nursing work after returning to their posts. In particular, the clinical nurse specialists with senior professional titles participated in more specialized nursing work projects, such as continuous improvement of orthopedic nursing quality, and so on. The influence of having attained different educational levels on the specialized nursing work of orthopedic nurse specialists was not significant.

Conclusions: The orthopedic nurse specialists carried out a series of specialized nursing work after returning to their posts, which not only helps to improve the quality of orthopedic nursing, but also assists in promoting the popularization and homogenization of new knowledge and skills in orthopedic nursing in the Jiangsu Province.
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http://dx.doi.org/10.21037/apm-21-2291DOI Listing
September 2021

Glycyrrhiza acid micelles loaded with licochalcone A for topical delivery: Co-penetration and anti-melanogenic effect.

Eur J Pharm Sci 2021 Sep 30;167:106029. Epub 2021 Sep 30.

School of Traditional Chinese Medicine, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou 510515, China. Electronic address:

The co-penetration of micellar vehicles and the encapsulated drugs into the skin layers, as well as the mechanisms underlying the penetration enhancement have not been clearly elucidated. We developed licochalcone A (LA)-loaded glycyrrhiza acid (GA) (GA+LA) micelles for topical delivery of LA into the epidermis. The in vitro co-penetration, penetration pathways, mechanism of interaction between skin and the micelles, and the in vitro and in vivo whitening effect of GA+LA micelles were evaluated. Co-penetration and penetration pathways were visualized on the abdominal skin of rats model with confocal laser scanning microscopy (CLSM) using a nile blue A-labeled GA (GA-NB). We found that GA significantly increased the transport of LA into the skin predominantly via the hair follicles and GA mainly accumulated in the SC and epidermis, while LA was localized in the epidermis and dermis. Moreover, 73.4% of the LA deposited into the epidermis within 12 h and approximately 9.32% of the LA permeated across the SC in the form of entire micelles within 24 h. GA-NB+LA micelles disaggregated and accumulated in the specific skin layers, and the LA released from the carrier penetrated into deeper layers. Moreover, the GA+LA micelles promoted drug penetration via intracellular or intercellular routes by loosening the skin surface and enhancing fluidization through lipid distortion and keratin denaturation. Furthermore, GA+LA micelles exhibited synergistic whitening effect on B16 cells and UVB-exposed C57BL/6 mice. Collectively, GA micelles can enhance penetration of LA to the epidermis mainly via the hair follicles following topical application, and reduce skin pigmentation.
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http://dx.doi.org/10.1016/j.ejps.2021.106029DOI Listing
September 2021

Integrated Proteomics and Metabolomics Link Acne to the Action Mechanisms of Cryptotanshinone Intervention.

Front Pharmacol 2021 1;12:700696. Epub 2021 Sep 1.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

The label-free methods of proteomic combined with metabolomics were applied to explore the mechanisms of Cryptotanshinone (CPT) intervention in rats with acne. The model group consisted of rats given oleic acid (MC), then treated with CPT, while control groups did not receive treatment. The skin samples were significantly different between control, model and CPT-treated groups in hierarchical clustering dendrogram. Obvious separations of the skin metabolic profiles from the three groups were found through PCA scoring. In total, 231 and 189 differentially expressed proteins (DEPs) were identified in MC and CPT groups, respectively. By the KEGG analysis, five protein and metabolite pathways were found to be significantly altered. These played important roles in response to oleic acid-induced acne and drug treatment. CPT could negatively regulate glycolysis/gluconeogenesis and histidine metabolisms to decrease keratinocyte differentiation and improve excessive keratinization and cellular barrier function. CPT could down-regulate the IL-17 signaling pathway and regulate the acne-driven immune response of sebum cells. The biosynthesis of unsaturated fatty acids metabolism, glycerophospholipid metabolism and linoleic acid pathways could significantly alter sebum production and control sebaceous gland secretion after CPT treatment. The gap junction was up-regulated after CPT treatment and the skin barrier turned back to normal. Krt 14, Krt 16 and Krt 17 were significantly down-regulated, decreasing keratinization, while inflammatory cell infiltration was improved by down-regulation of Msn, up-regulation of linoleic acid and estrogen pathways after CPT treatment. These results propose action mechanisms for the use of CPT in acne, as a safe and potential new drug.
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http://dx.doi.org/10.3389/fphar.2021.700696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440807PMC
September 2021

Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice.

Elife 2021 Sep 16;10. Epub 2021 Sep 16.

Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Wuhan, China.

Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of the central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological, and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, for example, celastrol, might be a novel strategy for colorectal cancer treatment.
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http://dx.doi.org/10.7554/eLife.67535DOI Listing
September 2021

How size, edge shape, functional groups and embeddedness influence the electronic structure and partial optical properties of graphene nanoribbons.

Phys Chem Chem Phys 2021 Sep 22;23(36):20695-20701. Epub 2021 Sep 22.

School of Chemistry and Chemical Engineering, Qufu Normal University, P. R. China.

The armchair and zigzag edge shape makes graphene nanoribbons (GNRs) exhibit interest in different applications. However, the relationship between influencing factors and properties is not clear. Herein, the many-body Green's function theory and the TDDFT method are used to investigate the effect of size, edge shape and functional groups on the electronic and optical properties of GNRs and h-BN-embedded GNRs. We find that ZGNRs have a smaller band gap and absorption edge than AGNRs having the same size and functional groups. The relationship between S and T is mainly determined by the size and edge shape of GNRs, while the redox ability of water splitting mainly relies on the kind of the functional group. When h-BN is embedded in GNRs, the edge shape of GNRs and the contact part between two substances control the direction of electron transfer in both the ground state and the excited state. These results can provide theoretical support for further improvements and applications of GNRs.
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http://dx.doi.org/10.1039/d1cp02689eDOI Listing
September 2021

EGFR-IL-6 Signaling Axis Mediated the Inhibitory Effect of Methylseleninic Acid on Esophageal Squamous Cell Carcinoma.

Front Pharmacol 2021 30;12:719785. Epub 2021 Jul 30.

Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Epidemiological and experimental evidence indicate that selenium is associated with a reduced risk of some cancers, including esophageal cancer. However, the exact mechanism is still unclear. In the present study, we used esophageal squamous cell carcinoma (ESCC) cell lines and animal models to explore the anti-cancer mechanism of methylseleninic acid (MSA). Firstly, MSA treatment dramatically attenuated Epidermal Growth Factor Receptor (EGFR) protein expression but did not alter mRNA levels in ESCC cells. On the contrary, EGFR overexpression partly abolished the inhibitory effect of MSA. With a microRNA-array, we found MSA up-regulated miR-146a which directly targeted EGFR, whereas miR-146a inhibitor antagonized MSA-induced decrease of EGFR protein. We further used 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumor mice model to evaluate the inhibitory effect of MSA . MSA treatment significantly decreased the tumor burden and EGFR protein expression in tumor specimens. Furthermore, MSA treatment inhibited EGFR pathway and subsequntly reduced Interleukin-6 (IL-6) secretion in the supernatant of cancer cell lines. MSA-induced IL-6 suppression was EGFR-dependent. To further evaluate the association of IL-6 and the anti-tumor effect of MSA on esophageal cancer, we established the 4NQO-induced esophageal tumor model in IL-6 knock-out (IL-6 KO) mice. The results showed that IL-6 deficiency did not affect esophageal tumorigenesis in mice, but the inhibitory effect of MSA was abolished in IL-6 KO mice. In conclusion, our study demonstrated that MSA upregulated miR-146a which directly targeted EGFR, and inhibited EGFR protein expression and pathway activity, subsequently decreased IL-6 secretion. The inhibitory effect of MSA on esophageal cancer was IL-6 dependent. These results suggested that MSA may serve as a potential drug treating esophageal cancer.
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http://dx.doi.org/10.3389/fphar.2021.719785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363297PMC
July 2021

A Skin Lipidomics Study Reveals the Therapeutic Effects of Tanshinones in a Rat Model of Acne.

Front Pharmacol 2021 10;12:675659. Epub 2021 Jun 10.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

Tanshinone (TAN), a class of bioactive components in traditional Chinese medicinal plant Salvia miltiorrhiza, has antibacterial and anti-inflammatory effects, can enhance blood circulation, remove blood stasis, and promote wound healing. For these reasons it has been developed as a drug to treat acne. The purpose of this study was to evaluate the therapeutic effects of TAN in rats with oleic acid-induced acne and to explore its possible mechanisms of action through the identification of potential lipid biomarkers. In this study, a rat model of acne was established by applying 0.5 ml of 80% oleic acid to rats' back skin. The potential metabolites and targets involved in the anti-acne effects of TAN were predicted using lipidomics. The results indicate that TAN has therapeutic efficacy for acne, as supported by the results of the histological analyses and biochemical index assays for interleukin (IL)-8, IL-6, IL-β and tumor necrosis factor alpha. The orthogonal projection of latent structure discriminant analysis score was used to analyze the lipidomic profiles between control and acne rats. Ninety-six potential biomarkers were identified in the skin samples of the acne rats. These biomarkers were mainly related to glycerophospholipid and sphingolipid metabolism, and the regulation of their dysfunction is thought to be a possible therapeutic mechanism of action of TAN on acne.
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http://dx.doi.org/10.3389/fphar.2021.675659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223585PMC
June 2021

A comparison of modified laparoscopic uterine suspension and vaginal hysterectomy with sacrospinous ligament fixation for treating pelvic organ prolapse.

Am J Transl Res 2021 15;13(5):5672-5678. Epub 2021 May 15.

Department of Gynaecology, The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.

Objectives: To compare the efficacy and adverse events between modified laparoscopic uterine suspension and vaginal hysterectomy and sacrospinous ligament fixation.

Methods: The study reviewed the clinical data of 50 postmenopausal patients who underwent modified laparoscopic uterine suspension (the hysteropexy group) and 50 patients who underwent vaginal hysterectomy with sacrospinous ligament fixation (the hysterectomy group) conducted by the same group of surgeons (2018.1-2019.6) retrospectively. We compared the two groups' baseline characteristics, perioperative details, complications, and POP-Q values before the operations and at 12 months after the operations. The effects on quality of life according to valid questionnaires (PFIQ-7 and PFDI-20) were compared. The patients were followed up for 12 months.

Results: There were no significant differences in the perioperative details or baseline characteristics, except that more cases of concurrent vaginal wall (anterior and posterior) and concurrent perineal repair were observed in the hysteropexy group than in the hysterectomy group (9 versus 0, =0.02; 33 versus 6, < 0.001). The anatomical measures of points Ba, Bp, and C ( < 0.001), and the quality of life measures (P < 0.001 for PFIQ-7 and PFDI-20) after the operations exhibited significant improvements in the two groups. The total vaginal lengths (TVL) were dramatically decreased after the surgery in the hysterectomy group, but no differences were observed in the hysteropexy group. The two groups didn't show a significant difference in the recurrence of prolapse anatomically or symptomatically, but a dramatically higher number of patients in the hysterectomy group were found to have experienced postoperative vaginal bleeding, excessive granulation tissue and right buttock pain.

Conclusions: The postoperative outcomes, anatomical results, and improvement of function and symptoms of modified laparoscopic uterine suspension were similar to those of vaginal hysterectomy with sacrospinous ligament fixation. Moreover, modified laparoscopic uterine suspension had fewer postoperative complications, so it could be used as an additional choice for POP, although the long-term outcomes haven't been determined yet.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205734PMC
May 2021

Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma.

Int J Biol Sci 2021 1;17(2):430-447. Epub 2021 Jan 1.

Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.
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http://dx.doi.org/10.7150/ijbs.54014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893581PMC
January 2021

Cetuximab enhances the anti-tumor function of macrophages in an IL-6 dependent manner.

Life Sci 2021 Feb 24;267:118953. Epub 2020 Dec 24.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address:

Aims: Cetuximab improves the survival of patients with advanced colorectal cancer (CRC). However, how cetuximab affects the tumor microenvironment has not been sufficiently understood. This study was to investigate whether cetuximab could inhibit the pro-tumor function of tumor-associated macrophages (TAMs) by suppressing the EGFR/IL-6 pathway.

Main Methods: The azoxymethane/dextran sodium sulfate (AOM/DSS) and tumor xenograft mouse models were used to assess the effect of cetuximab on TAMs. Flow cytometry, Western blotting, RT-qPCR, and ELISA were used to assess the prevalence of M2 and M1 phenotypes. Publicly available datasets of CRC patients were used to assess the relevance of EGFR and IL-6 expression as prognostic indicators.

Key Findings: The two mouse models showed that cetuximab could attenuate the pro-tumor function of TAMs and decrease tumor burden. Cetuximab repolarized TAMs from M2-like to M1-like phenotypes, mainly by suppressing the IL-6 expression through NFκB and STAT3 pathways. Analysis of public scRNA-seq data indicated EGFR was mainly expressed on the surface of macrophage infiltration into tumor microenvironment. The public transcriptomics datasets showed that the expression level of IL-6 was positively correlated with EGFR in CRC patients, and PROGgeneV2 analysis indicated that IL-6 and CD206 both predicted poor recurrence-free and overall survival of CRC patients. Furthermore, the inhibition efficacy of cetuximab was significantly attenuated in IL-6 knockout CRC mice model.

Significance: These results indicate a new macrophage-based molecular mechanism explaining the effect of cetuximab in treatment of colorectal cancer.
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http://dx.doi.org/10.1016/j.lfs.2020.118953DOI Listing
February 2021

[Magnetic Resonance Imaging Features of Ovarian Thecoma].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2020 Oct;42(5):651-657

Department of Pathology,Maternity and Child Care Hospital,Huzhou,Zhejiang 313000,China.

Objective To investigate the magnetic resonance imaging(MRI)findings of ovarian thecomas and improve the accuracy of preoperative MRI diagnosis of the disease.Methods A retrospective analysis of 48 patients with ovarian thecoma confirmed by operation and pathology was performed.According to the maximum diameter,the lesions were divided into≥5 cm and <5 cm groups and analyzed in terms of location,size,shape,boundary,cystic necrosis,TWI/TWI signals,DWI characteristics,enhancement features,and pelvic effusion.The diagnostic score was evaluated by MRI(the highest score was 6 points).Results All the 48 lesions were single.In the≥5 cm group(=39),the tumor boundary was clear in 37 cases and unclear in 2 cases;necrosis was found in 35 cases;TWI showed equal signals in 23 cases and equal low signals in 16 cases;TWI showed equal signals in 7 cases,equal low signals in 23 cases,and slightly higher signals in 9 cases;DWI showed high signals in 23 cases and mixed high signals in 16 cases;dynamic enhanced scans showed slight enhancement in all cases;33 patients had different degrees of pelvic fluid;score evaluation showed 6 points in 33 cases,5 points in 2 cases,4 points in 2 cases,and 3 points in 2 cases.In the <5 cm group(=9),all lesions had clear boundaries;cystic necrosis was seen in 3 cases;TWI showed equal signals in 3 cases and equal low signals in 6 cases;TWI showed equal signals in 2 cases,equal low signals in 4 cases,and slightly higher signal in 3 cases;DWI showed high signals;the dynamic enhancement of the lesions showed slight enhancement in 8 cases and significant enhancement in one case;a small amount of pelvic fluid was seen in 4 cases;score evaluation revealed 6 points in 3 cases,5 points in 1 case,4 points in 4 cases,and 3 points in 1 case.The incidences of pelvic effusion(=6.680,=0.010)and cyst necrosis(=14.109,<0.001)in the≥5 cm group were significantly higher than those in the <5 cm group.The number of patients with cystic lesions with elevated estrogen levels was significantly higher than that of patients without cystic lesions(=5.847,=0.016;contingency coefficeient=0.330).Conclusions Large ovarian thecomas have high or mixed high signals on DWI;they are often accompanied by pelvic fluid and cystic necrosis,and the cystic necrosis is common and has small involvement.For small ovarian thecomas,DWI often reveals high signals,and cystic necrosis is rare.MRI score evaluation combined with patient's age and other factors is helpful to improve the accuracy of preoperative diagnosis.
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http://dx.doi.org/10.3881/j.issn.1000-503X.11841DOI Listing
October 2020

Recent advances in graphene-family nanomaterials for effective drug delivery and phototherapy.

Expert Opin Drug Deliv 2021 01 31;18(1):119-138. Epub 2020 Dec 31.

School of Traditional Chinese Medicine, Southern Medical University , Guangzhou, China.

Introduction: Owing to the unique properties of graphene, including large specific surface area, excellent thermal conductivity, and optical absorption, graphene-family nanomaterials (GFNs) have attracted extensive attention in biomedical applications, particularly in drug delivery and phototherapy.

Areas Covered: In this review, we point out several challenges involved in the clinical application of GFNs. Then, we provide an overview of the most recent publications about GFNs in biomedical applications, including diverse strategies for improving the biocompatibility, specific targeting and stimuli-responsiveness of GFNs for drug delivery, codelivery of drug and gene, photothermal therapy, photodynamic therapy, and multimodal combination therapy.

Expert Opinion: Although the application of GFNs is still in the preclinical stage, rational modification of GFNs with functional elements or making full use of GFNs-based multimodal combination therapy might show great potential in biomedicine for clinical application.
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http://dx.doi.org/10.1080/17425247.2020.1798400DOI Listing
January 2021

EGFR targeting enhances the efficiency of chemotherapy through inhibiting IRE1α-XBP1s pathway in colorectal cancer cells.

J Cancer 2020 18;11(15):4464-4473. Epub 2020 May 18.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Targeting EGFR combined with chemotherapy is one of the most valuable therapeutic strategies in colorectal cancer. However, resistance remains a major obstacle to improve efficacy. IRE1α-XBP1s signaling pathway is activated in many malignant tumors, and plays important roles in chemoresistance. Therefore, IRE1α-XBP1s might be a potential target to overcome the chemoresistance in colorectal cancer. In this study, we detected the activation of IRE1α-XBP1s signaling in patient cancer tissues and colorectal cancer cell lines. The phosphorylation level of IRE1α and the spliced XBP1s were aberrantly elevated in colorectal cancer, and IRE1α-XBP1s signaling activation was correlated with high EGFR expression. By overexpression of EGFR protein or activation by EGF treatment, we found that EGFR activation could enhance the phosphorylation of IRE1α and spliced XBP1s expression. On the contrary, inhibition of EGFR decreased the IRE1α-XBP1s signaling. Further, we examined the downstream signaling pathways regulated by EGFR. Inhibition of ERK activity could reverse the EGFR induced IRE1α-XBP1s activation. Co-IP confirmed the physical interaction of ERK and IRE1α. Cell growth and colony formation assay showed that the inhibition of IRE1α activity could suppress EGFR driven colorectal cancer cell proliferation. Furthermore, we found that oxaliplatin could activate IRE1α-XBP1s signaling, and combination with cetuximab partially reversed the activation. Inhibition of EGFR signaling could enhance the efficacy of oxaliplatin in vitro and in vivo. Our results showed that IRE1α RNase activity is aberrantly elevated in colorectal cancer, and EGFR signaling could activate IRE1α/XBP1s possibly through EGFR-MEK-ERK pathway. IRE1α-XBP1s pathway might involve in EGFR driven tumor cell proliferation. Cetuximab could partially recover oxaliplatin-induced IRE1α-XBP1s activation, and therefore enhance the anti-tumor efficacy of oxaliplatin. Our findings declare a new mechanism that targeting EGFR could inhibit chemotherapy-induced IRE1α-XBP1s activation and therefore enhance the efficacy.
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http://dx.doi.org/10.7150/jca.44234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255363PMC
May 2020

Formulation and Characterization of a 3D-Printed Cryptotanshinone-Loaded Niosomal Hydrogel for Topical Therapy of Acne.

AAPS PharmSciTech 2020 May 31;21(5):159. Epub 2020 May 31.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.

Cryptotanshinone (CPT) is an efficacious acne treatment, while niosomal hydrogel is a known effective topical drug delivery system that produces a minimal amount of irritation. Three-dimensional (3D) printing technologies have the potential to improve the field of personalized acne treatment. Therefore, this study endeavored to develop a 3D-printed niosomal hydrogel (3DP-NH) containing CPT as a topical delivery system for acne therapy. Specifically, CPT-loaded niosomes were prepared using a reverse phase evaporation method, and the formulation was optimized using a response surface methodology. In vitro characterization showed that optimized CPT-loaded niosomes were below 150 nm in size with an entrapment efficiency of between 67 and 71%. The CPT-loaded niosomes were added in a dropwise manner into the hydrogel to formulate CPT-loaded niosomal hydrogel (CPT-NH), which was then printed as 3DP-CPT-NH with specific drug dose, shape, and size using an extrusion-based 3D printer. The in vitro release behavior of 3DP-CPT-NH was found to follow the Korsmeyer-Peppas model. Permeation and deposition experiments showed significantly higher rates of transdermal flux, Q, and CPT deposition (p < 0.05) compared with 3D-printed CPT-loaded conventional hydrogel (3DP-CPT-CH), which did not contain niosomes. In vivo anti-acne activity evaluated through an acne rat model revealed that 3DP-CPT-NH exhibited a greater anti-acne effect with no skin irritation. Enhanced skin hydration, wide inter-corneocyte gaps in the stratum corneum and a disturbed lipid arrangement may contribute towards the enhanced penetration properties of CPT. Collectively, this study demonstrated that 3DP-CPT-NH is a promising topical drug delivery system for personalized acne treatments.
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http://dx.doi.org/10.1208/s12249-020-01677-1DOI Listing
May 2020

Self-Stabilized Giant Aggregates in Water from Room-Temperature Ionic Liquids with an Asymmetric Polar-Apolar-Polar Architecture.

J Phys Chem B 2020 Jun 26;124(22):4651-4660. Epub 2020 May 26.

Key Laboratory of Colloid and Interface Chemistry & Key Laboratory of Special Aggregated Materials, Shandong University, Ministry of Education, Jinan 250100, China.

We report the assembly of four imidazolium bromides, each of which bears a naphthyl on one side of the imidazolium cation and a branched alkyl chain on the other. This design creates a new type of amphiphilic ionic liquid with an apolar-polar-apolar structure and a low melting point (, <-20 °C), which has not been achieved by reported counterparts bearing linear alkyl chains. In solvent-free states, microphase segregation occurs where polar and apolar domains arrange bicontinuously as proved by molecular dynamics (MD) simulations. When dispersed in water, self-stabilized giant aggregates formed with ultrahigh colloidal stability (up to years). MD simulations provide clues of discrete bicontinuous phases within the giant aggregates. These newly discovered self-assemblies provide a heterogeneous reservoir that can accommodate guest molecules including the highly apolar fullerene C, paving the way for a wide range of potential applications.
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http://dx.doi.org/10.1021/acs.jpcb.0c02283DOI Listing
June 2020

Clinical and functional significance of CHK1-S, an alternatively spliced isoform of the CHK1 gene, in hepatocellular carcinoma.

J Cancer 2020 17;11(7):1792-1799. Epub 2020 Jan 17.

Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

Alternative splicing plays critical roles in many disease processes and splicing dysregulation is a hallmark of cancer. The different splicing isoforms may have significantly different effects on the malignant progression of cancer. Checkpoint kinase 1 (CHK1) is a serine/threonine kinase and regulates DNA damage response. In this study, we measured the expression of an alternative CHK1 transcript (CHK1-S, excluded exon 3) in hepatocellular carcinoma (HCC) tissues. Our results showed that CHK1-S was significantly upregulated in HCC tissues compared with paired adjacent noncancerous hepatic tissues. The levels of full-length CHK1(CHK1-L), CHK1-S and the ratio of CHK1-S/L in tumor tissue were associated with relapse free survival (RFS) of postoperative HCC patients, respectively, but not the levels of CHK1-L, CHK1-S and the ratio of CHK1-S/L in adjacent normal tissue. To further demonstrate the role of CHK1-S in HCC, CCK-8 assays, EdU incorporation assays and colony formation assays were used. The results showed that overexpression of CHK1-S significantly accelerated HCC cell proliferation, compared with CHK1-L. In addition, we found that serine-arginine protein kinase 1 (SRPK1), as an upstream regulator kinase of splicing factor, could upregulate the expression of CHK1-S and its expression level was significantly higher in HCC tumors than the paired normal tissues and was associated with the levels of CHK1-S (P=0.016). In conclusion, our study demonstrated that CHK1-S, acts as an oncogene, which was upregulated and associated with RFS in HCC patients. SRPK1 may mediate its mRNA splicing in HCC. All these data indicated that the expression of CHK1-S would have potential prognostic values and splicing kinase SRPK1 might be developed as therapeutic target in HCC.
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http://dx.doi.org/10.7150/jca.39443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052871PMC
January 2020

Revealing stable geometries and magic clusters of hexagonal boron nitride in the nucleation of chemical vapor deposition growth on Ni(111)/Cu(111) surfaces: a theoretical study.

Phys Chem Chem Phys 2020 Feb 5;22(7):4023-4031. Epub 2020 Feb 5.

Henan Key Laboratory of Materials on Deep-Earth Engineering, School of Materials Science and Engineering, Henan Polytechnic University, Henan 454003, China.

To improve the quality of chemical vapor deposition (CVD)-prepared hexagonal boron nitride (h-BN), it is essential to understand the growth mechanism, particularly to learn the structures as well as their stabilities and kinetic evolutions of the formed clusters in the initial growth stage. Herein, we performed systematic studies on the stabilities of various geometries of different-/identical-sized BN clusters on (111) surfaces of Ni and Cu by density functional theory simulations. The results show that the stable configurations of different-sized clusters are those containing the most normal hexagons composed with alternate B and N atoms. There exist ultra-stable magic clusters on the (111) surfaces of both the metals. On Ni(111), the geometries of the magic clusters are composed of hexagons arranged in the core-shell structure, while they contain tetragons on the Cu(111) surface. The ultra-high stabilities of the magic clusters can be attributed to the comprehensive effect from the core-shell structure, high symmetry, edged atoms, and adsorption sites. The stable geometries of different-sized clusters as well as magic clusters present the vital roles of metal substrates in CVD-synthesis of h-BN and provide instructive information in improving the quality of h-BN by selecting appropriate metal substrates.
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http://dx.doi.org/10.1039/c9cp06425gDOI Listing
February 2020

[Determination of glufosinate, aminomethylphosphonic acid, and glyphosate residues in farmland soil by post-column addition of alkali using high performance anion exchange chromatography-pulse amperometric detection].

Se Pu 2019 Sep;37(9):1004-1010

Zhongke PUYAN(Beijing) Science and Technology Co., Ltd., Beijing 100027, China.

A chromatographic method was developed for the determination of glufosinate (GLUF), aminomethylphosphonic acid (AMPA), and glyphosate (GLY) in farmland soil by the post-column addition of alkali using high performance anion exchange chromatography-pulse amperometric detection. Samples were extracted with 2 mmol/L sodium hydroxide solution, then filtered through a 0.22 μm membrane, and purified by a IC-C column and IC-Na column. Three target compounds and coexisting ions in the filtered solution were separated on an IonPacAS11-HC anion exchange column (250 mm×4 mm), and were detected by the post-column addition of alkali using pulse amperometric detection. Results showed that GLUF and GLY had good linearity in the range of 20.0-1000 μg/L, and AMPA had good linearity in the range of 5.0-400 μg/L, with correlation coefficients above 0.999. The limits of detection of GLUF, AMPA, and GLY were 0.08, 0.02, and 0.04 mg/kg, respectively, and the recoveries were in the range of 80.2%-106% with RSDs of 0.7%-5.0% (=6). The method provides strong anti-interference, high sensitivity, and accuracy, and can be adopted simply and quickly; therefore, it is suitable for detecting the residues of GLUF, AMPA, and GLY in farmland soil.
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http://dx.doi.org/10.3724/SP.J.1123.2019.03025DOI Listing
September 2019

Octreotide and Continuous Hemofiltration versus Continuous Hemofiltration Alone in Severe Acute Pancreatitis Complicated with Acute Respiratory Distress Syndrome.

J Coll Physicians Surg Pak 2019 Aug;29(8):785-787

Department of Gastroenterology, Huai'an Second People's Hospital and The Affiliated Huaian Hospital of Xuzhou Medical University, 223400, China.

The objective of this study was to compare effects of octreotide and continuous hemofiltration versus continuous hemofiltration alone in the treatment of severe acute pancreatitis (SAP) complicated with acute respiratory distress syndrome (ARDS). It was an experimental study carried out from April 2016 to April 2018. A total of 86 cases of SAP complicated with ARDS were randomly divided into group A and group B, with 43 cases in each group. Group A was given continuous hemofiltration alone, and group B was given continuous hemofiltration combined with octreotide. The research findings showed that serum tumor necrosis factor (TNF-α), interleukin-1 (IL-1), IL-6, IL-8, diamine oxidase (DAO), endotoxin, D-lactic acid levels and acute physiology and chronic health evaluation (APACHE II) and systemic inflammatory response syndrome (SIRS) scores of group B were lower than those of group A (all p<0.001) after treatment. There was no significant difference in mortality between two groups after 90 days of discharge (p=0.306). Compared with continuous hemofiltration alone, treatment with continuous hemofiltration plus octreotide is higher in efficiency, but did not translate into improved mortality.
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http://dx.doi.org/10.29271/jcpsp.2019.08.785DOI Listing
August 2019

SAE1 promotes human glioma progression through activating AKT SUMOylation-mediated signaling pathways.

Cell Commun Signal 2019 07 25;17(1):82. Epub 2019 Jul 25.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, No.17, 3rd Section of People's South Road, Chengdu, 610041, People's Republic of China.

Background: The SUMO-activating enzyme SAE1 is indispensable for protein SUMOylation. A dysregulation of SAE1 expression involves in progression of several human cancers. However, its biological roles of SAE1 in glioma are unclear by now.

Methods: The differential proteome between human glioma tissues and para-cancerous brain tissues were identified by LC-MS/MS. SAE1 expression was further assessed by immunohistochemistry. The patient overall survival versus SAE1 expression level was evaluated by Kaplan-Meier method. The glioma cell growth and migration were evaluated under SAE1 overexpression or inhibition by the CCK8, transwell assay and wound healing analysis. The SUMO1 modified target proteins were enriched from total cellular or tissue proteins by incubation with the anti-SUMO1 antibody on protein-A beads overnight, then the SUMOylated proteins were detected by Western blot. Cell apoptosis and cell cycle were analyzed by flow cytometry. The nude mouse xenograft was determined glioma growth and tumorigenicity in vivo.

Results: SAE1 is identified to increase in glioma tissues by a quantitative proteomic dissection, and SAE1 upregulation indicates a high level of tumor malignancy grade and a poor overall survival for glioma patients. SAE1 overexpression induces an increase of the SUMOylation and Ser473 phosphorylation of AKT, which promotes glioma cell growth in vitro and in nude mouse tumor model. On the contrary, SAE1 silence induces an obvious suppression of the SUMOylation and Ser473 phosphorylation of Akt, which inhibits glioma cell proliferation and the tumor xenograft growth through inducing cell cycle arrest at G2 phase and cell apoptosis driven by serial biochemical molecular events.

Conclusion: SAE1 promotes glioma cancer progression via enhancing Akt SUMOylation-mediated signaling pathway, which indicates targeting SUMOylation is a promising therapeutic strategy for human glioma.
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http://dx.doi.org/10.1186/s12964-019-0392-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659289PMC
July 2019

Multifunctional Pharmaceutical Effects of the Antibiotic Daptomycin.

Biomed Res Int 2019 27;2019:8609218. Epub 2019 May 27.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No.17, 3rd Section of People's South Road, Chengdu 610041, China.

Daptomycin (DAP), a cyclic lipopeptide produced by , is a novel antibiotic to clinically treat various Gram-positive pathogenic bacteria-induced infections. Although DAP has a strong broad-spectrum bactericidal effect, recently rare bacterial antibiotic resistance against DAP gradually arises. The review is to summarize the normal indications of DAP, its off-label usage against several clinical pathogen infections, the unique antibacterial mechanisms of DAP, and the combination of antibiotic therapies for highly DAP-resistant pathogens. More noticeably, rising evidences demonstrate that DAP has new potential activity of anticancer and immunomodulatory effects. So far the multifunctional pharmaceutical effects of DAP deserve to be further explored for future clinical applications.
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http://dx.doi.org/10.1155/2019/8609218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556800PMC
January 2020

MS-based strategies for identification of protein SUMOylation modification.

Electrophoresis 2019 11 27;40(21):2877-2887. Epub 2019 Jun 27.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, P. R. China.

Protein SUMOylation modification conjugated with small ubiquitin-like modifiers (SUMOs) is one kind of PTMs, which exerts comprehensive roles in cellular functions, including gene expression regulation, DNA repair, intracellular transport, stress responses, and tumorigenesis. With the development of the peptide enrichment approaches and MS technology, more than 6000 SUMOylated proteins and about 40 000 SUMO acceptor sites have been identified. In this review, we summarize several popular approaches that have been developed for the identification of SUMOylated proteins in human cells, and further compare their technical advantages and disadvantages. And we also introduce identification approaches of target proteins which are co-modified by both SUMOylation and ubiquitylation. We highlight the emerging trends in the SUMOylation field as well. Especially, the advent of the clustered regularly interspaced short palindromic repeats/ Cas9 technique will facilitate the development of MS for SUMOylation identification.
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http://dx.doi.org/10.1002/elps.201900100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899701PMC
November 2019

Mechanisms of white mustard seed (Sinapis alba L.) volatile oils as transdermal penetration enhancers.

Fitoterapia 2019 Oct 5;138:104195. Epub 2019 Jun 5.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address:

We investigated the transdermal drug permeation enhancement properties and associated mechanisms of white mustard (Sinapis alba L.) seed volatile oil (SVO). Using gas chromatography-mass spectrometry, we showed that SVO was composed primarily of allylisothiocyanate and isothiocyanatocyclopropane. Compared with azone, SVO had better penetration-enhancing effects on three model drugs (5-Fluorouracil, Osthole, and Paeonol), with each having different oil-water partition coefficients. Histopathology showed that SVO did not induce skin irritation when the concentration was lower than 2% (v/v), and it induced less irritation than azone. According to attenuated total reflection-Fourier transform infrared spectroscopy and transmission electron microscopy, SVO induced skin lipid structural disorder and increased the distance between the stratum corneum, which is beneficial to the penetration of drugs. Cellular experiments showed that SVO inhibited Ca-ATPase activity, increased intracellular Ca concentration, and changed the membrane potential in HaCaT cells, which promoted drug transfer into the skin. Our findings reveal that SVO is a safe and efficient natural product that has great potential as skin penetration enhancer.
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http://dx.doi.org/10.1016/j.fitote.2019.104195DOI Listing
October 2019

LKB1 and YAP phosphorylation play important roles in Celastrol-induced β-catenin degradation in colorectal cancer.

Ther Adv Med Oncol 2019 22;11:1758835919843736. Epub 2019 Apr 22.

Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 PanjiayuanNanli, Chaoyang District, P.O. Box 2258, 100021, Beijing, P. R. China State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, No.17, 3rd Section of People's South Road, Chengdu, 610041, P.R. China.

Wnt/β-catenin and Hippo pathways play essential roles in the tumorigenesis and development of colorectal cancer. We found that Celastrol, isolated from plant, exerted a significant inhibitory effect on colorectal cancer cell growth and , and further unraveled the molecular mechanisms. Celastrol induced β-catenin degradation through phosphorylation of Yes-associated protein (YAP), a major downstream effector of Hippo pathway, and also Celastrol-induced β-catenin degradation was dependent on liver kinase B1 (LKB1). Celastrol increased the transcriptional activation of LKB1, partially through the heat shock factor 1 (HSF1). Moreover, LKB1 activated AMP-activated protein kinase α (AMPKα) and further phosphorylated YAP, which eventually promoted the degradation of β-catenin. In addition, LKB1 deficiency promoted colorectal cancer cell growth and attenuated the inhibitory effect of Celastrol on colorectal cancer growth both and . Taken together, Celastrol inhibited colorectal cancer cell growth by promoting β-catenin degradation the HSF1-LKB1-AMPKα-YAP pathway. These results suggested that Celastrol may potentially serve as a future drug for colorectal cancer treatment.
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http://dx.doi.org/10.1177/1758835919843736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477772PMC
April 2019

Emerging microRNA biomarkers for colorectal cancer diagnosis and prognosis.

Open Biol 2019 01;9(1):180212

1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy , No. 17, 3rd Section of People's South Road, Chengdu 610041 , People's Republic of China.

MicroRNAs (miRNAs) are one abundant class of small, endogenous non-coding RNAs, which regulate various biological processes by inhibiting expression of target genes. miRNAs have important functional roles in carcinogenesis and development of colorectal cancer (CRC), and emerging evidence has indicated the feasibility of miRNAs as robust cancer biomarkers. This review summarizes the progress in miRNA-related research, including study of its oncogene or tumour-suppressor roles and the advantages of miRNA biomarkers for CRC diagnosis, treatment and recurrence prediction. Along with analytical technique improvements in miRNA research, use of the emerging extracellular miRNAs is feasible for CRC diagnosis and prognosis.
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http://dx.doi.org/10.1098/rsob.180212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367136PMC
January 2019

Little Antimicrobial Peptides with Big Therapeutic Roles.

Protein Pept Lett 2019 ;26(8):564-578

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University / Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.

Antimicrobial Peptides (AMPs) are short amphipathic biological molecules generally with less than 100 amino acids. AMPs not only present high bioactivities against bacteria, fungi or protists-induced infections, but also play important roles in anticancer activity, immune response and inflammation regulation. AMPs are classified as ribosomally synthesized, non-ribosomally synthesized and post-translationally modified, non-ribosomally synthesized ones and several synthetic or semisynthetic peptides according to their synthesis with or without the involvement of ribosomes. The molecular characterization and bioactivity action mechanisms are summarized for several ribosomally synthesized AMPs and main non-ribosomally synthesized members (cyclopeptides, lipopeptides, glycopeptides, lipoglycopeptides). We also analyze challenges and new strategies to overcome drug resistance and application limitations for AMP discovery. In conclusion, the growing novel small molecular AMPs have huge therapeutic potentials of antibacterial, antiviral, anticancer and immunoregulatory bioactivities through new techniquesdriven drug discovery strategy including bioinformatics prediction, de novo rational design and biosynthesis.
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http://dx.doi.org/10.2174/1573406415666190222141905DOI Listing
October 2019

Expression of Micro-RNA-492 (MiR-492) in Human Cervical Cancer Cell Lines is Upregulated by Transfection with Wild-Type P53, Irradiation, and 5-Fluorouracil Treatment In Vitro.

Med Sci Monit 2018 Oct 30;24:7750-7758. Epub 2018 Oct 30.

Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (mainland).

BACKGROUND The status of p53 is critical to the chemoradiosensitivity of cervical cancer cells. Wild-type p53 is essential to orchestrate the cellular response to cytotoxic stimuli. Our previous data illustrated that cervical cancer patients whose specimens overexpressed microR-492 (miR-492) were highly sensitive to concurrent chemoradiation. Although p53 activation has been reported to upregulate miR-492 by a miRNA profiling assay in lung cancer cells, the transcriptional regulation of miR-492 in cervical cancer cells remains poorly understood. Therefore, we aimed to decipher the relationship between p53 and miR-492 in cervical cancer cells. MATERIAL AND METHODS The expression of p53 and miR-492 in cervical cancer cell lines was measured by western blot and real-time PCR. After cells were transfected with wild-type p53 plasmid or were treated by irradiation and 5-fluorouracil (5-FU), the expression changes of p53 as well as miR-492 were examined by western blot and real-time PCR. The putative p53 binding site of miR-492 was first analyzed by bioinformatics tools, then validated by chromatin immunoprecipitation and dual-luciferase reporter assays. RESULTS We found that miR-492 was upregulated in cells with wild-type p53 compared to cells with mutant p53. Transfection of wild-type p53 plasmid or treatments with cytotoxic reagents including irradiation and 5-FU all induced miR-492 overexpression. Bioinformatics analysis and experimental validations further proved p53 interacted with miR-492 promoter directly. CONCLUSIONS In cervical cancer cells, p53 activated miR-492 expression transcriptionally.
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http://dx.doi.org/10.12659/MSM.911585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354641PMC
October 2018

Isoliquiritigenin suppresses human melanoma growth by targeting miR-301b/LRIG1 signaling.

J Exp Clin Cancer Res 2018 Aug 6;37(1):184. Epub 2018 Aug 6.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.

Background: Isoliquiritigenin (ISL), a natural flavonoid isolated from the root of licorice (Glycyrrhiza uralensis), has shown various pharmacological properties including anti-oxidant, anti-inflammatory and anti-cancer activities. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been reported as post-transcriptional regulators with altered expression levels in melanoma. This study aims to investigate the anti-melanoma effect of ISL and its potential mechanism.

Methods: We investigated the effect of ISL on the proliferation and apoptosis of melanoma cell lines with functional assays, such as CCK-8 assay, colony formation assay and flow cytometry. The protein level of apoptosis related genes were measured by western blotting. High-throughput genome sequencing was used for screening differentially expressed miRNAs of melanoma cell lines after the treatment of ISL. We performed functional assays to determine the oncogenic role of miR-301b, the most differentially expressed miRNA, and its target gene leucine rich repeats and immunoglobulin like domains 1 (LRIG1), confirmed by bioinformatic analysis, luciferase reporter assay, western blotting and immunohistochemical assay in melanoma. Immunocompromised mouse models were used to determine the role of miR-301b and its target gene in melanoma tumorigenesis in vivo. The relationship between miR-301b and LRIG1 was further verified in GEO data set and tissue specimens.

Results: Functional assays indicated that ISL exerted significant growth inhibition and apoptosis induction on melanoma cells. MiR-301b is the most differentially expressed miRNA after the treatment of ISL and significantly downregulated. The suppressive effect of ISL on cell growth is reversed by ectopic expression of miR-301b. Intratumorally administration of miR-301b angomir enhances the inhibitory effect of ISL on tumor growth in vivo. Bioinformatic analysis showed that miR-301b may target LRIG1, miR-301b suppresses the luciferase activity of reporter constructs containing 3'UTR of LRIG1 as well as the expression level of LRIG1. And the anti-cancer effect of ISL is mitigated when LRIG1 is silenced in vivo and in vitro. Analysis of the melanoma samples obtained from patients shows that LRIG1 is negatively correlated with miR-301b.

Conclusions: ISL may inhibit the proliferation of melanoma cells by suppressing miR-301b and inducing its target LRIG1.
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http://dx.doi.org/10.1186/s13046-018-0844-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091185PMC
August 2018
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