Publications by authors named "Lingmin Zhang"

66 Publications

Construction and evaluation of prognostic models for esophageal cancer patients with distant and non-distant metastases: providing a reference process for clinical diagnosis and treatment.

J Gastrointest Oncol 2021 Aug;12(4):1241-1254

Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Although the current treatment for esophageal cancer has great technological progress, the 5-year survival rate of patients is not optimistic. About 70% of patients with esophageal cancer are at an advanced stage at first diagnosis. These patients are prone to distant metastasis, and the prognosis is poor. Therefore, understanding the risk factors for distant metastasis in patients with esophageal cancer, combined with the prognosis of the patient, can aid in choosing the optimal diagnosis and treatment plan. Ultimately, it will improve the patient's survival time and quality of life. This research aims to construct a model for the risk assessment of distant metastasis in patients with esophageal cancer and prognostic models for patients with distant and non-distant metastases.

Methods: The Surveillance Epidemiology and End Results (SEER) database was used to select patients with esophageal cancer from 2010 to 2015. The optimal cutoff point was selected for the age and tumor size variables using X-tile. The nomogram was constructed using R software (The R Foundation for Statistical Computing).

Results: Gender, grade, T stage, N stage, and tumor size were independent risk factors associated with distant metastasis in patients with esophageal cancer. The concordance index (C-index) of the nomogram prediction model for whether the patient will have distant metastasis was 0.609. Age, grade, T stage, N stage, and tumor size were independent risk factors affecting the prognosis without distant metastasis. The C-index of the nomogram prediction model for patients with distant metastases was 0.590. Age and T stage were independent risk factors affecting the prognosis of patients with distant metastases. The C-index of the nomogram prediction model was 0.543. The combination of radiotherapy, chemotherapy, and primary surgery yielded the best overall survival for both patients with distant metastases and patients with non-distant metastases.

Conclusions: A comprehensive assessment of the risk of distant metastasis in patients with esophageal cancer, combined with prognosis prediction, is necessary to provide patients with a reasonable treatment plan.
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http://dx.doi.org/10.21037/jgo-21-429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421894PMC
August 2021

Recent advances of mA methylation modification in esophageal squamous cell carcinoma.

Cancer Cell Int 2021 Aug 10;21(1):421. Epub 2021 Aug 10.

Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, China.

In recent years, with the development of RNA sequencing technology and bioinformatics methods, the epigenetic modification of RNA based on N-methyladenosine (mA) has gradually become a research hotspot in the field of bioscience. mA is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs). mA methylation modification can dynamically and reversibly regulate RNA transport, localization, translation and degradation through the interaction of methyltransferase, demethylase and reading protein. mA methylation can regulate the expression of proto-oncogenes and tumor suppressor genes at the epigenetic modification level to affect tumor occurrence and metastasis. The morbidity and mortality of esophageal cancer (EC) are still high worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common tissue subtype of EC. This article reviews the related concepts, biological functions and recent advances of mA methylation in ESCC, and looks forward to the prospect of mA methylation as a new diagnostic biomarker and potential therapeutic target for ESCC.
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http://dx.doi.org/10.1186/s12935-021-02132-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353866PMC
August 2021

Epigenetic inhibition assisted chemotherapeutic treatment of lung cancer based on artificial exosomes.

Pharmacol Res 2021 Sep 24;171:105787. Epub 2021 Jul 24.

The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and The State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address:

We adopted a novel strategy by combining histone deacetylase (HDAC) inhibitors with traditional chemotherapeutics to treat solid tumors. However, chemotherapeutics often have a narrow therapeutic index and need multiple administrations with undesired side effects that lead to the intolerance. To reduce the non-specificity of chemotherapeutics, targeted therapy was introduced to restrict such agents in the tumor with minimum effects on other tissues. We developed bioinspired artificial exosomes (AE), which enabled to deliver chemotherapeutics to the tumors effectively after systemic administration. AE were produced by incorporating membrane proteins from cancer cells into phospholipid liposomes that mimicked the plasma membrane. The synthesized AE were used for the delivery of broad-spectrum chemotherapeutic doxorubicin (DOX) and vorinostat (SAHA), an epigenetic inhibitor. The combination of DOX and SAHA showed synergistic effects on suppressing non-small cell lung cancer cells and xenograft tumors without apparent adverse effects. AE facilitated the delivery of drugs to tumor tissue and extended the retention time of drugs within tumors. Taken together, these studies suggest that the bioengineered artificial exosomes may serve as novel delivery strategy for chemotherapeutics to treat non-small cell lung cancer.
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http://dx.doi.org/10.1016/j.phrs.2021.105787DOI Listing
September 2021

Hybrid artificial cell-mediated epigenetic inhibition in metastatic lung cancer.

J Colloid Interface Sci 2021 Jun 14;603:319-332. Epub 2021 Jun 14.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address:

Hypothesis: Histone deacetylase inhibitors (HDACIs), such as vorinostat (suberoylanilide hydroxamic acid, SAHA), has become a promising approach for the treatment of metastatic lung cancer. However, HDACIs usually showed a short circulation lifetime, low specificity, and low bioavailability, which limited their therapeutic effect in this field. We supposed that the use of biomimetic nanoparticles enabled to overcome the disadvantages of HDACIs, and improved the inhibition of metastatic lung cancer.

Experiments: SAHA was encapsulated into a pH-sensitive core constructed with Poly(lactic-co-glycolic acid) (PLAG) and 1,2-dioleoyloxy-3-(trimethylammonium) propane (DOTAP), followed by the camouflage with hybrid membranes derived from red blood cells and metastatic NCI-H1299 lung cancer cells (HRPDS). The physical and chemical properties were characterized with Transmission electron microscope (TEM), Size & Zeta potential analyzer. The cellular uptake was analyzed with Confocal laser scanning microscope (CLSM) and Flow cytometry (FACS). The biological effect analysis was performed with Western blotting (WB), RNA-Sequencing (RNA-Seq), and ChIP-Sequencing (ChIP-Seq).

Findings: HRPDS exhibited enhanced circulation lifetime in vivo and homotypic targeting to metastatic cells in the metastatic foci, which induced significant suppression of lung cancer liver metastasis. Our work opens a new avenue for the treatment of metastatic lung cancer by epigenetic inhibition based on this style of biomimetic nanovehicle.
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http://dx.doi.org/10.1016/j.jcis.2021.06.066DOI Listing
June 2021

Comparative study of vitrectomy combined with internal limiting membrane peeling and vitrectomy combined with internal limiting membrane flap covering in idiopathic macular hole treatment: a meta-analysis and systematic review.

Ann Palliat Med 2021 May;10(5):5474-5482

The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China; Department of Ophthalmology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: To compare the therapeutic effects of vitrectomy (PPV) combined with the internal limiting membrane (ILM) flap coverage and PPV in combination with ILM peeling on the idiopathic large macular hole (MH), in order to better guide the treatment of large MH.

Methods: Searching was conducted within PubMed, Web of Science, Embase, CNKI, and Wanfang databases, and relevant pieces of literature between 2010 and 2020 published in English or Chinese were included.

Results: A total of 11 studies including 667 patients and 667 affected eyes were included; the effective rate of hole closure between the 2 groups were compared in 11 studies. Results exhibited 94.4% (286/303 eyes) in the test group (PPV combined with ILM flap coverage) and 85.8% (313/364 eyes) in the control group (PPV combined with ILM peeling) were closed. MH closure rates in the test group was superior to the control group [odds ratio (OR) =3.36, 95% confidence interval (CI): 1.88-6.01, P<0.001]. All 11 studies compared the preoperative and postoperative best corrected visual acuity (BCVA), with no significant difference in the preoperative test control group [standardized mean difference (SMD) =-0.18, 95% CI: -0.42 to 0.06, P=0.149]. The BCVA after surgery was better in the test group compared with the control group (SMD =-0.91, 95% CI: -1.43 to -0.40), P=0.001).

Discussion: Compared with PPV combined with ILM peeling, PPV combined with ILM flap coverage can significantly improve the MH closure rate and postoperative BCVA.
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http://dx.doi.org/10.21037/apm-21-871DOI Listing
May 2021

Response of antioxidant defense to oxidative stress induced by HO and NO in anammox bacteria.

Chemosphere 2021 Nov 28;282:131008. Epub 2021 May 28.

State Key Laboratory of Pollution Control and Resources Reuse, Shanghai Institute of Pollution Control and Ecological Security, College of Environmental Science and Engineering, Tongji University, Siping Road, Shanghai, 200092, PR China. Electronic address:

Exposure to the stressful environment results in excessive generation of reactive oxygen species (ROS) or reactive nitrogen species (RNS) in anaerobes, which causes deterioration of microbial activities in biological wastewater treatment systems. Although the genes involved in oxidative stress defense have been primarily identified in the genome of Candidatus Kuenenia stuttgartiensis (a typical anammox species), their function is still not verified. Therefore, the expression of putative antioxidation genes kat, sor, and sod in anammox bacteria was studied by in situ transcription and function validated by heterologous expression under the typical ROS (HO) and RNS (NO) stress. After HO and NO additions, the genes involved in the anammox central metabolism (nirS, hzsB, and hdh) were immediately down expressed consistent with the decreased anammox activity. However, the expression of putative antioxidation gene kat did not rise when exposed to HO; whereas, its encoding protein KAT enhanced the antioxidant actively of anammox bacteria by HO decomposition like the oxidoreductase enzyme catalase. The sod and sor gene were upregulated with NO treatment, and SOD and SOR can combine with NO and decrease its concentration efficiently. These confirmed the important role of kat, sod, and sor as ROS/RNS scavengers in anammox bacteria, with which anammox bacteria protect themselves when they are exposed to the stressful environment. These verified functional enzymes provide directions for the future regulation of anammox systems, which helps to mitigate the inhibitory effect of the stressful environment on anammox bacteria.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131008DOI Listing
November 2021

In vivo Multi-scale Photoacoustic Imaging Guided Photothermal Therapy of Cervical Cancer based on Customized Laser System and Targeted Nanoparticles.

Int J Nanomedicine 2021 15;16:2879-2896. Epub 2021 Apr 15.

The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Department of Biomedical Engineering, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China.

Background: Effective treatment strategy for cervical carcinoma is subject to the limitation of its anatomical location and histological characteristics. Comprehensive imaging before cervical carcinoma treatment is of great significance for the patients. Current imaging methods cannot meet the requirements of high resolution, deep imaging depth and non-invasive imaging at the same time. Fortunately, Photoacoustic imaging (PAI) is a novel imaging method that combines rich optical contrast, high ultrasonic spatial resolution, and deep penetration depth in a single modality. Moreover, PAI-guided photothermal therapy (PTT) by aid of targeting nanoparticles is an emerging and effective cancer treatment in recent years.

Methods: Here, strong near-infrared region (NIR) absorption-conjugated polymer PIIGDTS (PD) nanoparticles with folic acid (FA) modification (namely, PD-FA) that targeted at Hela cell were specifically designed as cervical tumor imaging contrast agents and photothermal agents.

Results: The obtained PD-FA nanoparticles exhibited admirable photoacoustic contrast-enhancing ability and desirable PTT behavior with the photothermal conversion efficiency as high as 62.6% in vitro. Furthermore, the PAI performance and PTT efficiency were tested in HeLa tumor-bearing nude mice after injection of PD-FA nanoparticles. In vivo multi-scale, PAI provided B-san and 3D dimension imaging for intuitive and comprehensive information of Hela tumor. Moreover, the Hela tumor can be completely eliminated within 18 days after PTT, with no toxicity and side effects.

Conclusion: In summary, PD-FA injection combined with PAI and PTT systems provides a novel powerful tool for early diagnosis and precise treatment of cervical cancer.
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http://dx.doi.org/10.2147/IJN.S301664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055284PMC
May 2021

Hypoxia-activated probe for NIR fluorescence and photoacoustic dual-mode tumor imaging.

iScience 2021 Mar 2;24(3):102261. Epub 2021 Mar 2.

Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, P. R. China.

Construction of tumor microenvironment responsive probe with more than one imaging modality, in particular toward hypoxia of solid tumors, is an appealing yet significantly challenging task. In this work, we designed a hypoxia-activated probe TBTO (Triphenylamine-Benzothiadiazole-Triphenylamine derivative featuring four diethylamino N-Oxide groups) for imaging. TBTO could undergo bioreduction in a hypoxic microenvironment to yield compound TBT sharing both near-infrared (NIR) aggregation-induced emission and strong twisted intramolecular charge transfer features, which endows the probe with excellent performance in NIR fluorescence and photoacoustic dual-mode tumor imaging. This study offers useful insights into designing a new generation agent for clinical cancer diagnosis.
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http://dx.doi.org/10.1016/j.isci.2021.102261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973868PMC
March 2021

Targeting SNHG3/miR-186-5p reverses the increased m6A level caused by platinum treatment through regulating METTL3 in esophageal cancer.

Cancer Cell Int 2021 Feb 17;21(1):114. Epub 2021 Feb 17.

Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi, China.

Background: Platinum-based chemotherapy is a mainstay for treating esophageal cancer patients. In this manuscript, we have provided clues for influence of platinum on overall m6A level and further investigated the potential regulatory mechanism.

Methods: qRT-PCR was used to measure SNHG3 and miR-186-5p expression; ELISA and western blot were used to measure the expression of METTL3. CCK8 was used to measure the cell proliferation rate. Caspase 3/7 activity was used to measure the apoptosis rate. Dual luciferase reporter gene assay and RNA pull down assay were used to investigate the potential crosstalk between miR-186-5p and SNHG3; and miR-186-5p and METTL3.

Results: m6A level was increased when treated with platinum (CDDP, CPB and L-OHP). Besides, SNHG3 expression was induced and miR-186-5p expression was suppressed by platinum. Furthermore, SNHG3 could promote the m6A level, however miR-186-5p inhibited the m6A level through targeting METTL3. SNHG3 interacts with miR-186-5p to negatively regulate the expression of miR-186-5p; and miR-186-5p might bind to the 3'UTR of METTL3 to regulate its expression.

Conclusion: Platinum can increase the overall m6A level of esophageal cancer. SNHG3/miR-186-5p, induced by platinum, was involved in regulating m6A level by targeting METTL3. Our manuscript has provided clues that regulating m6A level might be a novel way to enhance the platinum efficacy.
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http://dx.doi.org/10.1186/s12935-021-01747-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887820PMC
February 2021

The Anti-apoptotic Role of 3'-Untranslational Region in Response to Angiotensin II via Mcl1 Expression.

Front Cell Dev Biol 2020 5;8:593955. Epub 2021 Jan 5.

Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.

Myeloid cell leukemia 1 (Mcl1), an abundant protein in the myocardium, plays an essential role in fibrosis and anti-inflammation in cardiomyocytes to prevent heart failure. However, whether 3'-untranslated regions (3'-UTR) has the cardio-protecting function remains unclear. Down-regulation of Mcl1 was observed in adult mice heart tissues after Angiotensin II (Ang II) treatment. Consistent with results, the reduction of Mcl1 expression was identified in Ang II-treated neonatal cardiomyocytes. Mechanistically, 3'-UTR prevented Ang II-induced cardiac apoptosis via up-regulation of Mcl1 and an angiogenic factor with a G-patch domain and a forkhead-associated domain 1 (Aggf1), which plays cardiac-protective role. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving mRNAs' 3'-UTRs application.
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http://dx.doi.org/10.3389/fcell.2020.593955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813760PMC
January 2021

Increased levels of YKL-40 in patients with diabetes mellitus: a systematic review and meta-analysis.

Diabetol Metab Syndr 2021 Jan 15;13(1). Epub 2021 Jan 15.

Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang, China.

Background: Diabetes mellitus (DM) could be classified as type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) and others according to etiology and pathology. Diabetic nephropathy (DN) is one of the most serious complications of DM. YKL-40 is a marker of inflammation and some studies have indicated that DM was related with inflammation. The objective of our study is to perform a systematic review and meta-analysis to confirm the relationship between YKL-40 and DM as well as DN.

Methods: Pubmed, Embase, CNKI and Chinese wanfang databases were searched for eligible studies by two independent authors. Studies were included in this meta-analysis if they fulfilled the following inclusion criteria: (1) a study involving the role of YKL-40 in DM (or DN) designed as a case-control study or cohort study; (2) the data of serum YKL-40 levels were available; (3) studies were published in English or Chinese. Finally, twenty-five studies were included in this meta-analysis.

Results: Compared with healthy controls, DM patients had significantly higher levels of YKL-40 (DM: SMD = 1.62, 95% CI 1.08 to 2.25, P = 0.000; GDM: SMD = 2.85, 95% CI 1.01 to 4.70, P = 0.002). Additionally, DM patients with different degree of albuminuria had significantly higher levels of YKL-40 compared with healthy controls (normoalbuminuria: SMD = 1.58, 95% CI 0.59 to 2.56, P = 0.002; microalbuminuria: SMD = 2.57, 95% CI 0.92 to 4.22, P = 0.002; macroalbuminuria: SMD = 2.69, 95% CI 1.40 to 3.98, P = 0.000) and serum YKL-40 levels increased with increasing severity of albuminuria among DM patients (microalbuminuria vs normoalbuminuria: SMD = 1.49, 95% CI 0.28 to 2.71, P = 0.016; macroalbuminuria vs microalbuminuria: SMD = 0.93, 95% CI 0.34 to 1.52, P = 0.002).

Conclusions: Our current meta-analysis demonstrates that serum level of YKL-40 is increased in DM and positively associated with the severe degree of albuminuria. Therefore, we suggest that YKL-40 could be considered to be detected, along with other inflammatory markers, if DM, especially DN, is suspected.
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http://dx.doi.org/10.1186/s13098-021-00624-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809835PMC
January 2021

Decreased Indian hedgehog signaling activates autophagy in endometriosis and adenomyosis.

Reproduction 2021 02;161(2):99-109

Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.

Indian hedgehog (Ihh) signaling regulates endometrial receptivity and is an indispensable mediator of embryonic implantation. Hedgehog signaling is known to regulate autophagy, and aberrant regulation of autophagy is critically implicated in the pathogenesis of endometriosis and adenomyosis. However, potential dysregulation of Ihh signaling and its role in autophagy modulation in these diseases remain obscure. In this study, we found that components of Ihh signaling were significantly decreased, whereas the autophagy marker protein, LC3BII, was significantly increased in endometrial tissues of women with endometriosis or adenomyosis. Inhibition of Ihh signaling with the small-molecule inhibitor GANT61 or Gli1 silencing in primary endometrial stromal cells increased autophagic activity, as measured by LC3 turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy. Furthermore, we observed that GANT61 treatment significantly attenuated hydrogen peroxide-induced cell death, whereas disruption of autophagy with chloroquine diminished this effect. Collectively, these findings reveal that Ihh signaling is suppressed in endometrial tissues of patients with endometriosis or adenomyosis. This abnormal decrease may contribute to endometrial autophagy activation, which may promote aberrant survival of endometrial cells in ectopic sites in these two gynecological diseases.
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http://dx.doi.org/10.1530/REP-20-0172DOI Listing
February 2021

High-Performance Dual Combination Therapy for Cancer Treatment with Hybrid Membrane-Camouflaged Mesoporous Silica Gold Nanorods.

ACS Appl Mater Interfaces 2020 Dec 16;12(52):57732-57745. Epub 2020 Dec 16.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.

Conventional chemotherapy usually induces significant side effects due to its inability to discriminate between cancer and normal cells. Moreover, the efficacy of cancer elimination is still unsatisfied. Here, we fabricated a nanocomposite enabling high-performance dual combination therapy (chemo/photothermal therapy). This style of novel nanocomposites was constructed with doxorubicin (DOX)-loaded mesoporous silica gold (MSG) nanorods, which were further camouflaged with hybrid membranes derived from HeLa cells and red blood cells (HRMSGD). The hybrid membrane-camouflaged structure showed enhanced circulation lifetime and cell line-specific delivery of chemotherapeutics both in vitro and in vivo. The dual combination therapy by HRMSGD showed an unattainable therapeutic effect, compared with a single treatment, and inhibited tumor growth significantly. Furthermore, the nanoplatforms were photoacoustic-responsive, which showed real-time and noninvasive tracking capability. The present study established nanoplatforms with hybrid cell membrane-camouflaged multifunctional gold nanorods, which realized the combination of homotypic targeting, noninvasive tracking, chemotherapy, and photothermal therapy. To the best of our knowledge, this is the first study to use a natural membrane to camouflage mesoporous silica-modified gold nanorods, which opened a new avenue for cancer treatment.
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http://dx.doi.org/10.1021/acsami.0c18287DOI Listing
December 2020

Circular RNAs and esophageal cancer.

Cancer Cell Int 2020 3;20:362. Epub 2020 Aug 3.

Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061 Shaanxi China.

As a new kind of RNA, circular RNA (circRNA) is a endogenous non-coding RNA with circular structure, which has the characteristics of universality, stability, conservatism and specificity. CircRNA can specifically bind to microRNAs (miRNAs) in the form of competitive endogenous RNA, thus directly or indirectly regulating the expression of related genes. In addition to the role of sponge, circRNA also regulates parental gene expression, transcriptional translation and protein modification; and it can be used as a biomarker to develop potential diagnosis and treatment methods and evaluate prognosis. Due to changes in dietary habits and genetic factors, the morbidity and mortality of esophageal cancer (EC) in the world are still high, and are prone to early metastasis. Although the diagnosis and treatment techniques have been improved in recent years, the early diagnosis of EC is not common, and the 5-year survival rate of patients is still very low. This article reviews the function and significance of circRNA and discusses the research progress of circRNA as biomarkers in EC.
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http://dx.doi.org/10.1186/s12935-020-01451-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397661PMC
August 2020

MiR-142-3p enhances chemosensitivity of breast cancer cells and inhibits autophagy by targeting HMGB1.

Acta Pharm Sin B 2020 Jun 16;10(6):1036-1046. Epub 2019 Nov 16.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.

MiR-142-3p has been reported to act as a tumor suppressor in breast cancer. However, the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown. Here, we found that miR-142-3p was significantly downregulated in the doxorubicin (DOX)-resistant MCF-7 cell line (MCF-7/DOX). MiR-142-3p overexpression increased DOX sensitivity and enhanced DOX-induced apoptosis in breast cancer cells. High-mobility group box 1 (HMGB1) is a direct functional target of miR-142-3p in breast cancer cells and miR-142-3p negatively regulated HMGB1 expression. Moreover, overexpression of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by miR-142-3p up-regulation. In conclusion, miR-142-3p overexpression may inhibit autophagy and promote the drug sensitivity of breast cancer cells to DOX by targeting HMGB1. The miR-142-3p/HMGB1 axis might be a novel target to regulate the drug resistance of breast cancer patients.
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http://dx.doi.org/10.1016/j.apsb.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332808PMC
June 2020

Micro RNA-363 inhibits esophageal squamous cell carcinoma progression by directly targeting sperm-associated antigen 5.

J Int Med Res 2020 Jun;48(6):300060520932795

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China.

Objective: Micro RNA (miR)-363 has many important biological functions in cancers, but its roles in esophageal squamous cell carcinoma (ESCC) remain unclear.

Methods: We used reverse transcription PCR to quantify the expression of miR-363 in 80 ESCC tissues and analyzed its relationship with clinicopathological factors and overall survival. The effects of miR-363 on cell proliferation, apoptosis, and invasion were detected using the MTT assay, flow cytometry, and Transwell invasion assays, respectively. Further, we investigated the post-transcriptional regulation of sperm-associated antigen 5 (SPAG5) expression by miR-363 using luciferase reporter assays. Finally, the effects of SPAG5 on miR-363 were studied by SPAG5 overexpression.

Results: miR-363 expression was decreased in both ESCC specimens and cell lines, compared with controls, and correlated with lymph node metastasis and tumor differentiation. Low miR-363 expression was identified as an independent prognostic factor for ESCC. miR-363 overexpression decreased ESCC cell proliferation and invasion and increased apoptosis, while the opposite was seen after miR-363 inhibition. Moreover, SPAG5 was identified as a direct target of miR-363, and the reintroduction of SPAG5 restored miR-363-induced effects.

Conclusions: miR-363 acts as a tumor suppressor by post-transcriptionally regulating SPAG5 expression, suggesting its potential as a diagnostic biomarker and therapeutic target for ESCC.
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http://dx.doi.org/10.1177/0300060520932795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323308PMC
June 2020

Artificial Platelets for Efficient siRNA Delivery to Clear "Bad Cholesterol".

ACS Appl Mater Interfaces 2020 Jun 11;12(25):28034-28046. Epub 2020 Jun 11.

Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.

Low-density lipoprotein cholesterol (LDL-C) is usually considered as a "bad cholesterol" for it is one of the major risk factors for coronary heart disease. As a scavenger of LDL-C, the low density lipoprotein receptor (LDLR) binds with LDL-C in the liver. However, the protein levels and function of LDLR are regulated by Proprotein convertase subtilisin/kexin type 9 (PCSK9). Loss of PCSK9 induces the increase of LDLR levels and reduction of plasma LDL-C. Here, we developed a novel style of artificial platelets with biomimetic properties, high stability, and long circulation which enabled the efficient delivery of siRNA targeting Pcsk9. The bioinspired nanoparticles induced Pcsk9 mRNA reduction by 66% in vitro. For studies, the nanoparticles accumulated in the liver to reduce Pcsk9 transcription, which results in ∼28% reduction in plasma LDL-C concentrations with negligible effects on either high density lipoprotein cholesterol (HDL-C) or triglycerides (TGs). These results demonstrated the use of artificial platelets to deliver siRNA and induce effective RNAi therapeutics to specifically lower LDL-C which provides a potential strategy to lower PCSK9 and treat hypercholesterolemia.
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http://dx.doi.org/10.1021/acsami.0c07559DOI Listing
June 2020

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer.

Cell Death Dis 2020 04 14;11(4):232. Epub 2020 Apr 14.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.

Although angiogenesis inhibitors targeting VEGF/VEGFR2 have been applied for tumor therapy, the outcomes are still unsatisfactory. Thus, it is urgent to develop novel angiogenesis inhibitor for cancer therapy from new perspectives. Identification of novel angiogenesis inhibitor from natural products is believed to be one of most promising strategy. In this study, we showed that pristimerin, an active agent isolated from traditional Chinese herbal medicine Celastrus aculeatus Merr, was a novel tumor angiogenesis inhibitor that targeting sonic hedgehog (Shh)/glioma associated oncogene 1 (Gli1) signaling pathway in non-small cell lung cancer (NSCLC). We showed that pristimerin affected both the early- and late-stage of angiogenesis, suggesting by that pristimerin inhibited Shh-induced endothelial cells proliferation, migration, invasion as well as pericytes recruitment to the endothelial tubes, which is critical for the new blood vessel maturation. It also suppressed tube formation, vessel sprouts formation and neovascularization in chicken embryo chorioallantoic membrane (CAM). Moreover, it significantly decreased microvessel density (MVD) and pericyte coverage in NCI-H1299 xenografts, resulting in tumor growth inhibition. Further research revealed that pristimerin suppressed tumor angiogenesis by inhibiting the nucleus distribution of Gli1, leading to inactivation of Shh/Gli1 and its downstream signaling pathway. Taken together, our study showed that pristimerin was a promising novel anti-angiogenic agent for the NSCLC therapy and targeting Shh/Gli1 signaling pathway was an effective approach to suppress tumor angiogenesis.
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http://dx.doi.org/10.1038/s41419-020-2425-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156472PMC
April 2020

Homotypic Targeting Delivery of siRNA with Artificial Cancer Cells.

Adv Healthc Mater 2020 05 17;9(9):e1900772. Epub 2020 Mar 17.

Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.

The camouflage with cell membrane bestows nanoparticles with cell-like functions, such as specific recognition, long blood circulation, and immune escaping. For cancer therapy, the nanoparticles camouflaged with cancer cell membrane (CCM) from homologous cells show homotypic targeting delivery of small molecule compounds, photosensitizers, or enzymes to the tumors. However, effective gene therapy encounters difficulties by this approach due to the properties of nucleic acids. Herein, a cancer cell-like gene delivery system is developed using an excellent polymer poly(β-amino ester) (PBAE) to condense small interfering RNA (siRNA) (targeting to Plk1 gene) into nanoparticles (PBAE/siPlk1) as the core, which is further camouflaged with CCM. These novel biomimetic nanoparticles CCM/PBAE/siPlk1 (CCMPP) demonstrate highly specific targeting to homotypic cancer cells, effective downregulation of PLK1 level, and inducing apoptosis of cancer cells. Based on the homotypic binding adhesion molecules on the CCM, the cellular internalization and homotypic-targeting accumulation to the tumors are clearly improved. CCMPP induces highly efficient apoptosis of cancer cells both in vitro and in vivo and results in significant tumor inhibition. The artificial cancer cells with homotypic properties can serve as a biomimetic delivery system for cancer-targeted gene therapy.
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http://dx.doi.org/10.1002/adhm.201900772DOI Listing
May 2020

Assessment of ovarian reserve by serum anti-Müllerian hormone in patients with systemic lupus erythematosus: a meta-analysis.

Ann Palliat Med 2020 Mar 3;9(2):207-215. Epub 2020 Mar 3.

Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou 318020, China.

Background: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune and cyclophosphamide (CYC) is often used in the therapy of SLE. Anti-Müllerian hormone (AMH) is expressed in the ovarian granulosa cells and is a reliable biomarker for ovarian reserve. Recent studies have showed that SLE patients have lower serum AMH levels and CYC has a negative influence on ovarian reserve. But the results are conflicting in other studies. The objective of our study is to perform a systemic review and metaanalysis to confirm the relationship between SLE and ovarian reserve reflected by serum AMH levels as well as the effect of CYC on ovarian reserve of SLE patients.

Methods: PubMed, Embase, Web of Science, CNKI, CHINESE WANFANG, China Science and Technology Database (VIP) databases were searched for eligible studies by two independent authors. Studies comparing serum AMH levels between SLE patients and healthy controls as well as serum AMH levels between SLE patients with and without the treatment of CYC were extracted. All statistical analyses were performed with STATA 12.0.

Results: Totally 19 studies including 1,272 SLE patients and 555 healthy controls were included in our study. In a comparison of serum AMH levels between SLE patients and healthy controls, the pooled SMD was -0.79 (95% CI, -1.41 to -0.18) (P<0.05), indicating a significantly lower serum level of AMH in SLE patients. The results were repeated in subgroup analyses by region, diagnostic criteria of SLE and AMH detection methods. The therapy of CYC in SLE patients had a negative influence on serum AMH levels with the pooled SMD of -0.58 (95% CI, -0.87 to -0.30) (P<0.05).

Conclusions: SLE is related to increased risk of decreased ovarian reserve and the treatment of CYC can do harm to ovarian reserve.
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http://dx.doi.org/10.21037/apm.2020.02.11DOI Listing
March 2020

Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators.

Acta Pharm Sin B 2020 Feb 17;10(2):313-326. Epub 2019 Sep 17.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.

Overexpression of exogenous lineage-determining factors succeeds in directly reprogramming fibroblasts to various cell types. Several studies have reported reprogramming of fibroblasts into induced cardiac progenitor cells (iCPCs). CRISPR/Cas9-mediated gene activation is a potential approach for cellular reprogramming due to its high precision and multiplexing capacity. Here we show lineage reprogramming to iCPCs through a dead Cas9 (dCas9)-based transcription activation system. Targeted and robust activation of endogenous cardiac factors, including GATA4, HAND2, MEF2C and TBX5 (G, H, M and T; GHMT), can reprogram human fibroblasts toward iCPCs. The iCPCs show potentials to differentiate into cardiomyocytes, smooth muscle cells and endothelial cells . Addition of MEIS1 to GHMT induces cell cycle arrest in G2/M and facilitates cardiac reprogramming. Lineage reprogramming of human fibroblasts into iCPCs provides a promising cellular resource for disease modeling, drug discovery and individualized cardiac cell therapy.
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http://dx.doi.org/10.1016/j.apsb.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016296PMC
February 2020

Relationships among retinal/choroidal thickness, retinal microvascular network and visual field in high myopia.

Acta Ophthalmol 2020 Sep 6;98(6):e709-e714. Epub 2020 Feb 6.

School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China.

Purpose: To determine the relationships among retinal/choroidal thickness, retinal microvascular network and visual field in high myopia.

Methods: This cross-sectional study included a total of 62 subjects, comprising 31 eyes with high myopia and 31 eyes with emmetropia or low myopia. Optical coherence tomography was used to quantify the thickness of ganglion cell complex (GCC), inner nuclear layer and outer plexiform layer (INOPL), outer retinal layer (ORL) and choroid layer (ChL). Optical coherence tomography angiography was used to quantify the superficial vessel density (SVD) and deep vessel density (DVD). Retinal light sensitivity (RLS) was measured by microperimetry-1 (MP1). The inner ring (1-1.75 mm), the outer ring (1.75-2.5 mm) and the whole ring (1-2.5 mm) around the macula were analysed and compared between the two groups. Pearson correlation analysis was performed to analyse the relationship among them.

Results: In the highly myopic group, the thinning of retinal/choroidal thickness and the decrease in retinal vessel density and RLS were found when compared to the emmetropia or low myopia (p < 0.05). Decreased RLS was correlated with decreased ORL thickness (r = -0.469, p = 0.008) and choroid thickness (r = 0.398, p = 0.030). There was no correlation between retinal microvascular network parameters and RLS (p > 0.05), but DVD showed a negative correlation with ORL (r = -0.474, p = 0.007).

Conclusion: Early visual field defects in highly myopic eyes may be influenced by the ORL loss and defect of choroidal circulation. The deep retinal microvascular network may have a compensatory action in the hypoxic setting of high myopia.
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http://dx.doi.org/10.1111/aos.14372DOI Listing
September 2020

All-trans-retinal induces autophagic cell death via oxidative stress and the endoplasmic reticulum stress pathway in human retinal pigment epithelial cells.

Toxicol Lett 2020 Apr 10;322:77-86. Epub 2020 Jan 10.

Central Laboratory, Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China. Electronic address:

Failure of all-trans-retinal (atRAL) clearance contributes to retina degeneration. However, whether autophagy can be activated by excess atRAL accumulation in retinal pigment epithelial (RPE) cells is not known. This study showed that atRAL provoked mitochondria-associated reactive oxygen species (ROS) production, activated the nuclear factor (erythroid-derived 2)-like 2 and apoptosis in a human RPE cell line, ARPE-19 cells. Moreover, we found that autophagic flux was functionally activated after atRAL treatment. The antioxidant N-acetylcysteine attenuated the expression of autophagy markers, suggesting that ROS triggered atRAL-activated autophagy. In addition, autophagic cell death was observed in atRAL-treated RPE cells, while inhibition of autophagy with 3-methyladenine or LC3, Beclin1, p62 silencing ameliorated atRAL-induced cytotoxicity. Suppression of autophagy quenched mitochondrial ROS and inhibited HO-1 and γ-GCSh expression, indicating that atRAL-activated autophagy enhances intracellular oxidative stress, thereby promoting RPE cell apoptosis. Furthermore, we found that inhibiting endoplasmic reticulum (ER) stress suppressed atRAL-induced mitochondrial ROS generation, subsequently attenuated autophagy and apoptosis in RPE cells. Taken together, these results suggest that atRAL-induced oxidative stress and ER stress modulate autophagy, which may contribute to RPE degeneration. There may be positive feedback regulatory mechanisms between atRAL-induced oxidative stress and autophagy or ER stress.
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http://dx.doi.org/10.1016/j.toxlet.2020.01.005DOI Listing
April 2020

Expression and association of IL-21, FBXL20 and tumour suppressor gene PTEN in laryngeal cancer.

Saudi J Biol Sci 2019 Dec 16;26(8):2048-2051. Epub 2019 Aug 16.

Department of Clinical Laboratory, the First Hospital of Jilin University, Changchun 130000, China.

Objective: To study the expression of three genes IL-21, FBXL20 and tumour suppressor gene PTEN in laryngeal cancer; analyse the differences in their expression in laryngeal cancer and adjacent tissues; by using pEGFP-N1-IL21 and pGPU/GFP/Neo-FBXL20 expression vectors, to analyse the characteristics in their expression in laryngeal cancer cells outside the body as well as the associations among them.

Methods: The expression of the three genes in laryngeal cancer and adjacent tissues from 30 cases and in normal laryngeal tissues from 20 healthy persons was detected with the RT-PCR; laryngeal cancer cell line (HEp-2 cells) transfection was also performed with the pEGFP-N1-IL21 and pGPU/GFP/Neo-FBXL20 expression vectors we constructed, to detect the mRNA expression of the three genes. Cell proliferation, apoptosis and cell cycle were measured by the MTT assay.

Results: The results of RT-PCR showed that the expression of IL-21 and FBXL20 was up-regulated in laryngeal cancer, while the expression of tumour suppressor gene PTEN was significantly decreased (p < 0.01). In HEp-2 cells transfected with pGPU/GFP/Neo-IL-21 and pGPU/GFP/Neo-FBXL20 expression vectors, the mRNA expression of PTEN was restored to some extent (p < 0.05); in addition, the ability of HEp-2 cells in proliferation and invasion was also reduced.

Conclusions: IL-21 and FBXL20 genes are important in the occurrence and development of laryngeal cancer; the expression of PTEN gene can suppress laryngeal cancer, and there's a certain association among IL-21, FBXL20 and PTEN.
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http://dx.doi.org/10.1016/j.sjbs.2019.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923488PMC
December 2019

Molecular cloning and characterization of a cathepsin L-like cysteine protease of Angiostrongylus cantonensis.

Int J Biol Macromol 2020 Jun 19;153:1136-1146. Epub 2019 Nov 19.

Department of Parasitology, School of Medicine, Jinan University, No.601, Huangpu Avenue West, Guangzhou 510632, China. Electronic address:

Angiostrongylus cantonensis is a parasitic nematode dwelling in the heart and pulmonary arteries of rats, which can cause angiostrongyliasis in human by accidental infections, manifested as eosinophilic meningitis or meningoencephalitis. Cysteine proteases are the major class of endopeptidases that are expressed at a high level in A. cantonensis, which suggests it may play key roles in pathogenesis of the disease. In this study, the biological properties of the cathepsin L-like peptidase (Ac-cathL) of A. cantonensis were investigated. The Ac-cathL gene was identified from the fourth stage cDNA library of A. cantonensis, and then cloned and characterized by bioinformatics analysis and heterologous expression. The open reading frame (ORF) of Ac-cathL (1068 bp) encodes a protein of 355 amino acids with an estimated molecular weight of 58.0 kDa. Sequence analysis and multiple sequence alignment demonstrated that Ac-cathL resembles members of cathepsin L family of other parasites and mammals. Stage-dependent mRNA expression analysis showed that Ac-cathL transcripts were expressed in all stages of A. cantonensis, with the highest expression in female stage. The recombinant Ac-cathL (rAc-cathL) expressed in Escherichia coli exhibited protease activity in acidic pH as demonstrated by gelatin zymography, as well as hydrolytic activity against natural substrates, including BSA, human IgG and human fibrinogen. Immunolocalization revealed that Ac-cathL is localized in tegument of the 18 days post infection stage and uterus of the female adult stage. Therefore, these results implied that the Ac-cathL plays important roles in host tissue migration, nutrition uptake and immune evasion.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.10.243DOI Listing
June 2020

Function, Significance, and Regulation of Rap1b in Malignancy.

Crit Rev Eukaryot Gene Expr 2019 ;29(2):151-160

Department of Thoracic Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Ras-associated protein 1(Rap1) is a member of the RAS family of small G proteins and regulates several signal pathways involved in carcinogenesis. Rap1 consists of two highly homologous isoforms, Rap1a and Rap1b. Increasing data suggest that the deregulated activation of Rap1b is involved in a spectrum of malignancies. Accumulating evidence also indicates effects of Rap1b on cell proliferation, metastasis, angiogenesis, and treatment resistance. Rap1b overexpresses in many tumors and has prognostic values, which are regulated by A2br, miRNAs, and other upstream effectors. This article aims to review research progress in function, significance, and regulation of Rap1b in malignancy.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2019025997DOI Listing
February 2020

Linc-PINT acted as a tumor suppressor by sponging miR-543 and miR-576-5p in esophageal cancer.

J Cell Biochem 2019 12 28;120(12):19345-19357. Epub 2019 Aug 28.

Department of Radiotherapy, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

This manuscript aimed to investigate linc-PINT's role as a tumor suppressor and its downstream microRNAs (miRNAs) in esophageal cancer. Log-rank, Cox, and nomogram were used for survival analysis. Quantitative real-time polymerase chain reaction was used to evaluate the expression. Cell counting kit-8 was used for proliferation tests. As for in vivo experiments, low expression of linc-PINT was associated with better prognosis; besides, the nomogram indicated that linc-PINT, miR-543, and miR-576-5p served well in predicting the survival rate. As for the in vitro experiments, linc-PINT could directly regulate miR-543 and miR-576-5p to inhibit the proliferation of Eca-109 cell line. In conclusion, linc-PINT-miR-543/miR-576-5p pathway could predict the prognosis and provide novel therapeutic targets for esophageal cancer.
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http://dx.doi.org/10.1002/jcb.28699DOI Listing
December 2019

Triple-Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases.

Angew Chem Int Ed Engl 2019 09 1;58(36):12404-12408. Epub 2019 Aug 1.

Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088 Xueyuan Rd, Nanshan District, Shenzhen, Guangdong, 518055, China.

A high level of low-density lipoprotein cholesterol (LDL-C) in the blood is a major risk factor for coronary heart disease. Herein, we present a triple-targeting strategy to generate a loss-of-function mutation in Pcsk9, which regulates plasma cholesterol levels, using a nanocarrier-delivered CRISPR/Cas9 system. Nuclear localization signal (NLS)-tagged Cas9 and Pcsk9-targeted single guide RNA (sgPcsk9) were complexed with gold nanoclusters (GNCs) modified with cationic HIV-1-transactivating transcriptor (TAT) peptide and further encapsulated in a galactose-modified lipid layer to target the nanoclusters to the liver. The resulting nanoclusters had an in vitro Pcsk9-editing efficiency of about 60 % and resulting in a decrease in plasma LDL-C in mice of approximately 30%. No off-target mutagenesis was detected in 10 sites with high similarity. This approach may have therapeutic potential for the prevention and treatment of cardiovascular disease without side effects.
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http://dx.doi.org/10.1002/anie.201903618DOI Listing
September 2019

Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells.

Toxicol Lett 2019 Sep 2;311:105-113. Epub 2019 May 2.

Central Laboratory, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China. Electronic address:

Excessive accumulation of cadmium (Cd) in retina plays an important role in tobacco smoking-associated age-related macular degeneration (AMD). Plenty of evidence has revealed that the retinal pigment epithelium (RPE) is the primary site of pathology in AMD. Our current study demonstrated that Cd induced apoptosis in a human RPE cell line ARPE-19 cells, as it dose-dependently caused cell viability loss and activated caspase-3. The reactive oxygen species (ROS) were confirmed to be important mediators for Cd-triggered cell death in ARPE-19 cells. We found that endoplasmic reticulum (ER) stress was activated as its marker BiP was remarkably upregulated by Cd-exposure. Whereas the antioxidants N-acetylcysteine (NAC) and Tempol significantly suppressed the expression of BiP and CHOP, suggesting that ROS generation is an early trigger of Cd-activated ER stress. Furthermore, we found that Cd-induced oxidative stress significantly increased autophagic flux and p62 expression. A temporal impact of Cd exposure is possibly existed in p62 expression in ARPE-19 cells. Moreover, an ER stress inhibitor salubrinal diminished Cd-induced LC3BII expression and attenuated cytotoxicity, indicating that ER stress mediates autophagy and was implicated in apoptosis of Cd-exposed ARPE-19 cells. However, CHOP expression may not exert impact on the regulation of Cd-caused autophagy. Additionally, inhibition of autophagy with si-Beclin 1 and 3-Methyladenine significantly ameliorated Cd-induced CHOP expression and cytotoxicity, indicating that autophagy was detrimental in Cd-accumulated ARPE-19 cells, and a positive feedback regulation mechanism may exist between Cd-triggered ER stress and autophagy. Taken together, these results suggest that Cd-caused ER stress and autophagy are implicated in RPE cell death associated retinopathies especially related to smoking.
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http://dx.doi.org/10.1016/j.toxlet.2019.05.001DOI Listing
September 2019

Evaluation of the Effectiveness of Clinical Pharmacists' Consultation in the Treatment of Infectious Diseases: A Single-Arm, Prospective Cohort Study.

Front Pharmacol 2019 1;10:187. Epub 2019 Mar 1.

Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, China.

With the implementation of Antimicrobial Stewardship Program, clinical pharmacists' consultation (CPC) for infectious diseases (ID) is gradually adopted by many hospitals in China. We conducted a cohort study to evaluate the effectiveness of CPC in ID treatment on patient outcomes and potential determinants. Based on a registry database, a prospective cohort study was conducted in Guizhou Provincial People's Hospital. The main exposure factor was whether clinician adopted the suggestion from clinical pharmacist. The outcome was effective response rate (ERR) of ID patients. The variables associated with the outcome (e.g., age, gender, severity of infection, liver function, and kidney function) were also prospectively recorded. A multilevel model was performed to analyze the factors related to ERR. A total of 733 ID inpatients were included in the final analysis according to the predesigned inclusion and exclusion criteria. The proportion of clinical pharmacists' suggestions adopted by clinicians and ERR were 88.13 and 69.03%, respectively. Significant data aggregation ( < 0.05) for individuals at the level of department was observed. According to the two-level variance component model, liver dysfunction ( = 0.649, 95% (: 0.432-0.976), severity of infection ( = 0.602, 95%: 0.464-0.781), and adopting the suggestion from pharmacist ( = 1.738, 95%: 1.028-2.940) had significant association with ERR. Our study suggests that the effect of CPC on ID treatment is significant. The policy/decision makers or hospital managers should be cognizant of the critical value of clinical pharmacists in ID treatment.
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http://dx.doi.org/10.3389/fphar.2019.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405418PMC
March 2019
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