Publications by authors named "Weiping Zheng"

83 Publications

Nanoparticles for Oral Cancer Diagnosis and Therapy.

Bioinorg Chem Appl 2021 23;2021:9977131. Epub 2021 Apr 23.

Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Oral cancer is the sixth most common malignant cancer, affecting the health of people with an unacceptably high mortality rate. Despite numerous clinical methods in the diagnosis and therapy of oral cancer (e.g., magnetic resonance imaging, computed tomography, surgery, and chemoradiotherapy), they still remain far from optimal. Therefore, an urgent need exists for effective and practical techniques of early diagnosis and effective therapy of oral cancer. Currently, various types of nanoparticles have aroused wide public concern, representing a promising tool for diagnostic probes and therapeutic devices. Their inherent physicochemical features, including ultrasmall size, high reactivity, and tunable surface modification, enable them to overcome some of the limitations and achieve the expected diagnostic and therapeutic effect. In this review, we introduce different types of nanoparticles that emerged for the diagnosis and therapy of oral cancers. Then, the challenges and future perspectives for nanoparticles applied in oral cancer diagnosis and therapy are presented. The objective of this review is to help researchers better understand the effect of nanoparticles on oral cancer diagnosis and therapy and may accelerate breakthroughs in this field.
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http://dx.doi.org/10.1155/2021/9977131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088384PMC
April 2021

Effects of S1PR2 antagonist on blood pressure and angiogenesis imbalance in preeclampsia rats.

Mol Med Rep 2021 Jun 21;23(6). Epub 2021 Apr 21.

Obstetrics Department, Jinhua Maternal and Child Health Hospital, Jinhua, Zhejiang 321000, P.R. China.

Preeclampsia (PE), a hypertensive multisystem disorder, can lead to increased maternal and fetal mortality and morbidity. Sphingosine‑1‑phosphate (S1P) plays various roles, depending on the cell type, by binding to S1P receptors (S1PR). The present study evaluated the changes of S1PRs and investigated the potential role of S1PRs in pregnancy‑induced hypertension. PE rats were established by reduced uterine perfusion pressure. The involvement of S1PR2 was evaluated using JTE‑013, a specific S1PR2 antagonist, in PE rats. After the treatment, inflammatory cytokines were evaluated using enzyme linked immunosorbent assay, and the expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) activation and endothelial nitric oxide synthase (eNOS) were evaluated by reverse transcription‑quantitative PCR and western blotting. Results showed that S1PR2, but not S1PR1 and S1PR3, was significantly increased in the serum and placenta tissues of PE rats. Notably, JTE‑013 significantly decreased blood pressure, attenuated infiltration of inflammatory cells and decreased inflammation, as indicated by the decreased expression of inflammatory cytokines, including tumor necrosis factor‑α, interleukin‑1β (IL‑1β) and IL‑6, in placental tissues. Mechanistic studies demonstrated that JTE‑013 significantly increased the expression of VEGF and decreased the expression of fms‑like tyrosine kinase 1 in placental tissue. Furthermore, JTE‑013 prevented iNOS activation and increased eNOS in placental tissue. In summary, the present study demonstrated that S1PR2 contributed to hypertension and angiogenesis imbalance in PE rats.
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http://dx.doi.org/10.3892/mmr.2021.12095DOI Listing
June 2021

Nutritional status and risk of contrast-associated acute kidney injury in elderly patients undergoing percutaneous coronary intervention.

Clin Exp Nephrol 2021 Apr 12. Epub 2021 Apr 12.

Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fuzhou, 350001, Fujian, China.

Background: This study aimed to investigate the connection between malnutrition evaluated by the Controlling Nutritional Status (CONUT) score and the risk of contrast-associated acute kidney injury (CA-AKI) in elderly patients who underwent percutaneous coronary intervention (PCI).

Methods: A total of 1308 patients aged over 75 years undergoing PCI was included. Based on the CONUT score, patients were assigned to normal (0-1), mild malnutrition (2-4), moderate-severe malnutrition group (≥ 5). The primary outcome was CA-AKI (an absolute increase in ≥ 0.3 mg/dL or ≥ 50% relative serum creatinine increase 48 h after contrast medium exposure).

Results: Overall, the incidence of CA-AKI in normal, mild, moderate-severe malnutrition group was 10.8%, 11.0%, and 27.2%, respectively (p < 0.01). Compared with moderate-severe malnutrition group, the normal group and the mild malnutrition group showed significant lower risk of CA-AKI in models adjusting for risk factors for CA-AKI and variables in univariate analysis (odds ratio [OR] = 0.48, 95% confidence interval [CI]: 0.26-0.89, p = 0.02; OR = 0.46, 95%CI: 0.26-0.82, p = 0.009, respectively). Furthermore, the relationship were consistent across the subgroups classified by risk factors for CA-AKI except anemia. The risk of CA-AKI related with CONUT score was stronger in patients with anemia. (overall interaction p by CONUT score = 0.012).

Conclusion: Moderate-severe malnutrition is associated with higher risk of CA-AKI in elderly patients undergoing PCI.
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http://dx.doi.org/10.1007/s10157-021-02061-4DOI Listing
April 2021

Upregulation of Associated with Cervical Cancer Incidence and Development.

Biomed Res Int 2021 3;2021:6663367. Epub 2021 Mar 3.

Department of Gynecology and Obstetrics, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China.

Background: Cervical cancer is a common malignant tumor of women. Using integrated bioinformatics, this study identified key disease-causing genes in cervical cancer that may provide effective biomarkers or therapeutic targets for early diagnosis and treatment.

Results: We used high-throughput sequencing data from the Gene Expression Omnibus (GEO) to identify new cervical cancer biomarkers. The GSE63678 dataset was downloaded. The data was analyzed via bioinformatics methods, and 61 differentially expressed genes were obtained. These differential genes were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analyses. GO analysis demonstrated that the basic biological functions of differential genes were mostly regulating cell division, mitotic nuclear division, and immune response. Analysis of the KEGG pathway showed the primary involved in the cell cycle, p53 signaling pathway, and cytokine-cytokine receptor interactions. Using TCGA database to query differential expression of differential genes in cervical cancer, the gene was found to be highly expressed. analysis of protein interactions using the STRING database revealed that interacts with many proteins. These findings were then validated with immunohistochemistry and qRt-PCR to confirm that is highly expressed in cervical cancer tissues. Cell function tests demonstrated that inhibition of expression could inhibit the proliferation and migration of cervical cancer HeLa and SiHa cells and promote apoptosis.

Conclusion: With comprehensive bioinformatics combined with clinical and cellular function analysis, is important to the development of cervical cancer. Targeting of this biomarker may improve the early diagnosis and treatment of cervical cancer.
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http://dx.doi.org/10.1155/2021/6663367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952153PMC
March 2021

Successful living donor liver transplantation plus domino-auxiliary partial orthotopic liver transplantation for pediatric patients with metabolic disorders.

Pediatr Surg Int 2020 Dec 10;36(12):1443-1450. Epub 2020 Oct 10.

Organ Transplantation Center, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, 300192, Tianjin, China.

Purpose: To investigate the efficacy of living donor liver transplantation (LDLT) plus domino-auxiliary partial orthotopic liver transplantation (D-APOLT) in pediatric patients with metabolic disorders.

Methods: From May 2017 to October 2018, two patients with ornithine aminotransferase deficiency (OTCD) and one patient with type I Crigler-Najjar syndrome (CNS1) received LDLT, their livers were prepared as donors for D-APOLT. Two patients with CNS1 received domino liver grafts from OTCD patients; one OTCD patient received a domino liver graft from a CNS1 patient.

Results: The mean follow-up was 26.6 months. The liver function and ammonia remained in the normal range at the end of the follow-up in all recipients. One D-APOLT patient experienced portal vein thrombosis 2 days after transplantation and required reoperation, this patient presented an imbalance of portal blood perfusion between the native and the domino liver at 8 months after liver transplant. The imbalance was improved by interventional radiology treatment. Two LDLT patients experienced early mild acute rejection.

Conclusions: The non-cirrhotic livers from pediatric patients with metabolic liver disease can be used as domino donor grafts for selected pediatric patients with different metabolic liver disease. D-APOLT achieves ideal recipient outcomes and provides a strategy to expand donor source for children.
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http://dx.doi.org/10.1007/s00383-020-04756-3DOI Listing
December 2020

Bis-Lactam Peptide [, +4]-Stapling with α-Methylated Thialysines.

Authors:
Bo Wu Weiping Zheng

Molecules 2020 Oct 1;25(19). Epub 2020 Oct 1.

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China.

Four bis-lactam [, +4]-stapled peptides with d- or l-α-methyl-thialysines were constructed on a model peptide sequence derived from p110α[E545K] and subjected to circular dichroism (CD) and proteolytic stability assessment, alongside the corresponding bis-lactam [, +4]-stapled peptide with l-thialysine. The % α-helicity values of these four stapled peptides were found to be largely comparable to each other yet greater than that of the stapled peptide with l-thialysine. An l-α-methyl-thialysine-stapled peptide built on a model peptide sequence derived from ribonuclease A (RNase A) was also found to exhibit a greater % α-helicity than its l-thialysine-stapled counterpart. Moreover, a greater proteolytic stability was demonstrated for the l-α-methyl-thialysine-stapled p110α[E545K] and RNase A peptides than that of their respective l-thialysine-stapled counterparts.
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http://dx.doi.org/10.3390/molecules25194506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582373PMC
October 2020

MiR-200b in heme oxygenase-1-modified bone marrow mesenchymal stem cell-derived exosomes alleviates inflammatory injury of intestinal epithelial cells by targeting high mobility group box 3.

Cell Death Dis 2020 06 25;11(6):480. Epub 2020 Jun 25.

Department of Organ Transplantation, Tianjin First Central Hospital, 300192, Tianjin, P.R. China.

Heme Oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) are effective to protect and repair transplanted small bowel and intestinal epithelial cells (IECs); however, the mechanism and the role of HO-1/BMMSCs-derived exosomes is unclear. In the present study, we aimed to verify that exosomes from a HO-1/BMMSCs and IEC-6 cells (IEC-6s) co-culture system could reduce the apoptosis of IEC-6s and decrease the expression of the tight junction protein, zona occludens 1, in the inflammatory environment. Using mass spectrometry, we revealed that high mobility group box 3 (HMGB3) and phosphorylated c-Jun NH2-terminal kinase (JNK), under the influence of differentially abundant proteins identified through proteomic analysis, play critical roles in the mechanism. Further studies indicated that microRNA miR-200b, which was upregulated in exosomes derived from the co-culture of HO-1/BMMSCs and IEC-6s, exerted its role by targeting the 3' untranslated region of Hmgb3 in this biological process. Functional experiments confirmed that miR-200b overexpression could reduce the inflammatory injury of IEC-6s, while intracellular miR-200b knockdown could significantly block the protective effect of HO-1/BMMSCs exosomes on the inflammatory injury of IEC-6s. In addition, the level of miR-200b in cells and exosomes derived from HO-1/BMMSCs stimulated by tumor necrosis factor alpha was significantly upregulated. In a rat small bowel transplantation model of allograft rejection treated with HO-1/BMMSCs, we confirmed that the level of miR-200b in the transplanted small bowel tissue was increased significantly, while the level of HMGB3/JNK was downregulated significantly. In conclusion, we identified that exosomes derived from HO-1/BMMSCs play an important role in alleviating the inflammatory injury of IECs. The mechanism is related to miR-200b targeting the abnormally increased expression of the Hmgb3 gene in IECs induced by inflammatory injury. The reduced level of HMGB3 then decreases the inflammatory injury.
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http://dx.doi.org/10.1038/s41419-020-2685-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316799PMC
June 2020

Prophylactic Strategy Against De Novo Hepatitis B Virus Infection for Pediatric Recipients Who Receive Hepatitis B Core Antibody-Positive Liver Grafts.

Liver Transpl 2021 01 1;27(1):96-105. Epub 2020 Dec 1.

Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, People's Republic of China.

The goal of this study was to evaluate the efficacy of a perioperative prophylactic strategy against de novo hepatitis B virus (HBV) infection in pediatric liver transplantation (LT) recipients with hepatitis B core antibody (HBcAb)-positive grafts. A total of 482 pediatric recipients transplanted between 2013 and 2017 were enrolled, and 170 recipients received HBcAb-positive liver grafts. The overall graft and recipient survival rates in HBcAb-positive and HBcAb-negative graft recipients were 91.8% versus 91.3% and 95.3% versus 94.2% at the end of follow-up. Preoperative hepatitis B surface antibody (HBsAb) titer ≥ 1000 IU/L and postoperative HBsAb titer ≥200 IU/L were our prophylactic targets for recipients receiving HBcAb-positive grafts. While 11 recipients developed de novo HBV infection, 10 received HBcAb-positive grafts. Both the preoperative and postoperative HBsAb targets were achieved in 78 recipients, the infection rate of de novo HBV was 1.3%; 24 recipients met the preoperative target, the infection rate was 4.2%; 52 recipients met the postoperative target, the infection rate was 1.9%; and 16 recipients met neither the preoperative nor postoperative HBsAb target, 43.8% of the recipients were infected with de novo HBV, which was significantly higher than the recipients who met both or either of the preoperative and postoperative targets. Split-liver grafts positive for HBcAb showed higher risk of de novo HBV infection. Postoperative application of lamivudine to recipients whose preoperative HBsAb titer < 1000 IU/L did not show preventive effect. Out of 11 infected recipients, 3 showed seroconversion under entecavir treatment. In conclusion, the graft and recipient survival rates were similar in pediatric LT recipients receiving HBcAb-positive or HBcAb-negative grafts. Our prophylactic strategy was effective for preventing de novo HBV infection in HBcAb-positive liver graft recipients.
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http://dx.doi.org/10.1002/lt.25813DOI Listing
January 2021

The overexpression of lncRNA MEG3 inhibits cell viability and invasion and promotes apoptosis in ovarian cancer by sponging miR-205-5p.

Int J Clin Exp Pathol 2020 1;13(5):869-879. Epub 2020 May 1.

Department of Gynecology, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University, School of Medicine No. 568 Zhongxing North Road, Yuecheng District, Shaoxing 201299, Zhejiang, China.

Purpose: Ovarian cancer is a common and fatal cancer in women. The long non-coding RNA (lncRNA) MEG3 was reported to affect the cellular processes of ovarian cancer, but the mechanisms remain unclear. Here, we aimed to explore the potential regulatory mechanism of MEG3 in ovarian cancer.

Materials And Methods: A reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was conducted to analyze the expression levels of MEG3 and miR-205-5p in tissues and cell lines. An MTT assay was utilized to determine the cell viability of ovarian cancer SKOV-3 and OVCAR-8 cells. A flow cytometry analysis was employed to disclose the ovarian cancer cell apoptosis. The migration and invasion of SKOV-3 and OVCAR-8 cells were examined using a Transwell assay. A bioinformatics analysis indicated miR-205-5p as a direct target of MEG3, and a luciferase reporter assay was conducted to validate the interaction between MEG3 and miR-205-5p.

Results: MEG3 was significantly down-regulated, while miR-205-5p was up-regulated in ovarian cancer tissues and cell lines. The overexpression of MEG3 and the knockdown of miR-205-5p inhibited cell viability, migration and invasion but promoted the apoptosis rate in ovarian cancer cells. MiR-205-5p was identified as a downstream gene of MEG3 and is negatively regulated by MEG3. The introduction of miR-205-5p reversed the up-regulation of MEG3-mediated suppression effects on cell viability, migration and invasion and increased cell apoptosis in ovarian cancer cells.

Conclusion: The overexpression of lncRNA MEG3 inhibits cell proliferation and cell invasion and promotes apoptosis in ovarian cancer by sponging miR-205-5p.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270692PMC
May 2020

Bibliometric Analysis of Pediatric Liver Transplantation Research in PubMed from 2014 to 2018.

Med Sci Monit 2020 Jun 4;26:e922517. Epub 2020 Jun 4.

Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China (mainland).

BACKGROUND Pediatric liver transplantation is used to treat children with end-stage liver disease. This study explored the research hotspots and bibliometric characteristics of pediatric liver transplantation through a variety of bibliometric analysis software. We conducted hotspot analysis to help determine important directions for future scientific research. MATERIAL AND METHODS The study samples were articles related to pediatric liver transplantation published in PubMed in the past 5 years. The high-frequency keywords are extracted by BICOMB software, and then a binary matrix and a common word matrix were constructed. Gcluto software was used to perform double-clustering and visual analysis on high-frequency words, and then we obtained hot area classification. Strategic coordinates are constructed using Excel. Citespace and VOSviewer software are used for further analysis and bibliometric data visualization. RESULTS A total of 36 high-frequency words were found in the 4118 studies. A peak map was drawn through double-cluster analysis. Biclustering analysis was used to calculate the concentricity and density of each hotspot. We obtained the top 10 countries/regions engaged in pediatric liver transplantation research. VOSviewer was used to visualize the co-author map. CONCLUSIONS We found 5 clusters and 7 aspects for pediatric liver transplantation. Additionally, calculation results showed that post-transplant lymphoproliferative disorder in pediatric patients and outcomes of multivisceral transplantation seem very promising. This conclusion is of great value for future exploratory research.
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http://dx.doi.org/10.12659/MSM.922517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294844PMC
June 2020

Acyl Cyanides as Bifunctional Reagent: Application in Copper-Catalyzed Cyanoamidation and Cyanoesterification Reaction.

J Org Chem 2020 Apr 2;85(8):5691-5701. Epub 2020 Apr 2.

Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou 341000, P. R. China.

Cu-catalyzed domino decyanation and cyanation reaction of acyl cyanides with amines or alcohols have been developed. The cyano sources were generated in situ via C-CN cleavage yielding the corresponding cyano substituted amides or esters in moderate to excellent yields. This approach features a cheap copper catalyst, domino decyanation and cyanation reaction, readily available starting materials, broad substrate scope, operational simplicity, and the potential for further transformation of the cyano group.
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http://dx.doi.org/10.1021/acs.joc.9b03500DOI Listing
April 2020

Review: The plant sirtuins.

Authors:
Weiping Zheng

Plant Sci 2020 Apr 4;293:110434. Epub 2020 Feb 4.

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address:

The sirtuin family of intracellular enzymes are able to catalyze a unique β-nicotinamide adenine dinucleotide (β-NAD)-dependent N-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Since 2000, the sirtuin family members have been identified in both prokaryotes and eukaryotes; tremendous accomplishments have also been achieved on the mechanistic and functional (pharmacological) understanding of the sirtuin-catalyzed deacylation reaction. Among the eukaryotic organisms, past research has been focused more on the yeast and mammalian sirtuins than on the plant sirtuins, however, the very presence of sirtuins in various plant species and the functional studies on plant sirtuins published thus far attest to the importance of this particular subfamily of eukaryotic sirtuins in regulating the growth and development of plants and their responses to biotic and abiotic stresses. In this review, an integrated and updated account will be presented on the biochemical, cellular, and functional profiles of all the plant sirtuins identified thus far. It is hoped that this article will also set a stage for expanded efforts in the identification, characterization, and functional interrogation of plant sirtuins; and the development and exploration of their chemical modulators (activators and inhibitors) in plant research and agriculture.
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http://dx.doi.org/10.1016/j.plantsci.2020.110434DOI Listing
April 2020

A bicyclic pentapeptide-based highly potent and selective pan-SIRT1/2/3 inhibitor harboring N-thioacetyl-lysine.

Bioorg Med Chem 2020 04 5;28(7):115356. Epub 2020 Feb 5.

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address:

Past few years have seen an active pursuit of the inhibitors for the deacylation catalyzed by the seven human sirtuins (i.e. SIRT1-7) as valuable chemical biological/pharmacological probes of this enzymatic deacylation and lead compounds for developing novel therapeutics for human diseases. In the current study, we prepared eight monocyclic and one bicyclic analogs of a linear pentapeptide-based potent (sub-μM IC's) pan-SIRT1/2/3 inhibitor Zheng laboratory discovered recently that harbors the catalytic mechanism-based SIRT1/2/3 inhibitory warhead N-thioacetyl-lysine at its central position. We found that the bicyclic analog exhibited largely comparable SIRT1/2/3 inhibitory potencies to those of the parent linear pentapeptide, however, the former is proteolytically much more stable than the latter. Moreover, the bicyclic analog displayed very weak inhibition against SIRT5/6/7, was cell permeable, and exhibited an anti-proliferative effect on the human SK-MEL-2 melanoma cells. This bicyclic analog could be a lead for the future development of more potent and still selective pan-SIRT1/2/3 inhibitors whose use in studies on human sirtuin biology, pharmacology, and medicinal chemistry could complement with the use of the potent inhibitors selective for a single human sirtuin.
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http://dx.doi.org/10.1016/j.bmc.2020.115356DOI Listing
April 2020

Risk factors of de novo hepatitis B virus infection in pediatric hepatitis B core antibody positive liver graft recipients under prophylactic therapy.

J Gastroenterol Hepatol 2020 May 24;35(5):827-832. Epub 2019 Oct 24.

Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China.

Background And Aim: We aim to investigate the risk factors of de novo hepatitis B virus (HBV) infection in pediatric liver transplantation recipients receiving hepatitis B core antibody positive grafts and to evaluate the efficacy of our prophylactic strategies.

Methods: One hundred thirty-nine pediatric recipients receiving hepatitis B core antibody positive grafts operated from September 2016 to September 2018 were retrospectively enrolled, and all the patients received prophylactic treatment to prevent de novo HBV infection. Donor and recipient features, operative information along with graft, and recipient outcomes were compared between recipients with or without de novo HBV infection. Univariate and multivariate analyses were applied to identify the risk factors of de novo HBV infection.

Results: The mean follow-up time was 23.5 ± 15.7 months, and the overall incidence of de novo HBV infection was 3.6%. Recipients with de novo HBV infection showed equal graft and recipient outcome compared with the recipients without de novo HBV infection during the follow-up time. Recipient preoperative hepatitis B surface antibody titer of < 1000 IU/L (odds ratio [OR] = 9.652, P = 0.024), graft HBV DNA of > 1000 copies (OR = 9.050, P = 0.032), and intraoperative fresh-frozen plasma transfusion of > 400 mL (OR = 10.462, P = 0.023) were identified as independent risk factors for de novo HBV infection.

Conclusion: Hepatitis B core antibody positive grafts can safely be used in pediatric liver transplantation under rational prophylactic therapy.
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http://dx.doi.org/10.1111/jgh.14869DOI Listing
May 2020

Application of pediatric donors in split liver transplantation: Is there an age limit?

Am J Transplant 2020 03 10;20(3):817-824. Epub 2019 Nov 10.

Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China.

The experience of using pediatric donors in split liver transplant is exceedingly rare. We aim to investigate the outcomes of recipients receiving split pediatric grafts. Sixteen pediatric recipients receiving split liver grafts from 8 pediatric donors < 7 years were enrolled. The donor and recipient characteristics, perioperative course, postoperative complications, and graft and recipient survival rates were evaluated. The mean follow-up time was 8.0 ± 2.3 months. The graft and recipient survival rates were 100%. The liver function remained in the normal range at the end of the follow-up time in all recipients. No life-threatening complications were seen in these recipients, and the only surgery-related complication was portal vein stenosis in 1 recipient. Cytomegalovirus infection was the most common complication (62.5%). The transaminase level was significant higher in extended right lobe recipients in the early postoperative days, but the difference vanished at the end of first week; postoperative complications and graft and recipient survival rates did not differ between left and right graft recipients. Notably, the youngest split donor graft (2.7 years old) was associated with ideal recipient outcomes. Split liver transplant using well-selected pediatric donors is a promising strategy to expand pediatric donor source in well-matched recipients.
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http://dx.doi.org/10.1111/ajt.15641DOI Listing
March 2020

Cyclic Tripeptide-based Potent and Selective Human SIRT5 Inhibitors.

Med Chem 2020 ;16(3):358-367

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China.

Background: SIRT5 is one of the seven members (SIRT1-7) of the mammalian sirtuin family of protein acyl-lysine deacylase enzymes. In recent years, important regulatory roles of SIRT5 in (patho)physiological conditions (e.g. metabolism and cancer) have been increasingly demonstrated. For a better biological understanding and therapeutic exploitation of the SIRT5- catalyzed deacylation reaction, more effort on identifying potent and selective SIRT5 inhibitors beyond those currently known would be rewarding.

Objective: In the current study, we would like to see if it would be possible to develop potent and selective SIRT5 inhibitory lead compounds with a novel structural scaffold than those of the currently known potent and selective SIRT5 inhibitors.

Methods: In the current study, six N-terminus-to-side chain cyclic tripeptides (i.e. 8-13) each harboring the thiourea-type catalytic mechanism-based SIRT5 inhibitory warhead Nε-carboxyethylthiocarbamoyl- lysine as the central residue were designed, synthesized by the Nα-9- fluorenylmethoxycarbonyl (Fmoc) chemistry-based solid phase peptide synthesis (SPPS) on the Rink amide 4-methylbenzhydrylamine (MBHA) resin, purified by the semi-preparative reversedphase high performance liquid chromatography (RP-HPLC), characterized by the high-resolution mass spectrometry (HRMS); and were evaluated by the in vitro sirtuin inhibition assay and the in vitro proteolysis assay.

Results: Among the cyclic tripeptides 8-13, we found that 10 exhibited a potent (IC50 ~2.2 μM) and selective (≥60-fold over the SIRT1/2/3/6-catalyzed deacylation reactions) inhibition against the SIRT5-catalyzed desuccinylation reaction. Moreover, 10 was found to exhibit a ~42.3-fold stronger SIRT5 inhibition and a greater proteolytic stability than its linear counterpart 14.

Conclusion: With a novel and modular structural scaffold as compared with those of all the currently reported potent and selective SIRT5 inhibitors, 10 could be also a useful and feasible lead compound for the quest for superior SIRT5 inhibitors as potential chemical/pharmacological probes of SIRT5 and therapeutics for human diseases in which SIRT5 desuccinylase activity is upregulated.
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http://dx.doi.org/10.2174/1573406415666190603101937DOI Listing
November 2020

A Method for Bischler-Napieralski-Type Synthesis of 3,4-Dihydroisoquinolines.

Org Lett 2019 04 8;21(8):2574-2577. Epub 2019 Apr 8.

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry , Tsinghua University , Beijing 100084 , P.R. China.

A new method for the Bischler-Napieralski-type synthesis of 3,4-dihydroisoquinolines was developed by a TfO-promoted tandem annulation from phenylethanols and nitriles. Its success was mainly due to the fact that a phenonium ion was formed in the process and practically functioned as a stable and reactive primary phenylethyl carbocation.
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http://dx.doi.org/10.1021/acs.orglett.9b00534DOI Listing
April 2019

Protective effects of CXCR3/HO‑1 gene‑modified BMMSCs on damaged intestinal epithelial cells: Role of the p38‑MAPK signaling pathway.

Int J Mol Med 2019 May 4;43(5):2086-2102. Epub 2019 Mar 4.

Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, P.R. China.

The purpose of the present study was to investigate whether bone marrow mesenchymal stem cells (BMMSCs) modified by CXC‑chemokine receptor type 3 (CXCR3) and heme oxygenase‑1 (HO‑1) genes can repair damaged intestinal epithelial cells in vitro, and the role of the p38 mitogen‑activated protein kinase (p38‑MAPK) pathway in this process. A model of intestinal epithelial crypt cell line‑6 (IEC‑6) damage was created, and BMMSCs were transfected with either the CXCR3 and/or HO‑1 gene in vitro. There were nine experimental groups in which the damaged IEC‑6 cells were co‑cultured with differentially‑treated BMMSCs and lymphocytes for 24 h. Reverse transcription‑quantitative polymerase chain reaction analysis, immunohistochemistry and a western blot analysis were performed to detect stem cell transfection, the repair of damaged intestinal epithelial cells and the expression of related molecules in the P38‑MAPK pathway, respectively. Crystal violet staining and live cell imaging were used to detect the chemotaxis of BMMSCs. Flow cytometry was used to detect T lymphocyte activity and the surface markers expressed on BMMSCs. An ELISA was used to quantify cytokine production. The adenovirus (Ad)‑CXCR3/MSCs exhibited the characteristics of stem cells and exhibited chemotaxis. The Ad‑CXCR3/MSCs and Ad‑(CXCR3 + HO)/MSCs exhibited increased expression of tight junction protein zonula occludens‑1 (ZO‑1) and anti‑proliferating cell nuclear antigen in the damaged IEC‑6 cells, and apoptosis of the damaged IEC‑6 cells was decreased. BMMSCs inhibited the phosphorylation of p38, in addition to downstream molecules of the p38MAPK signaling pathway. The Ad‑CXCR3/MSCs and Ad‑(CXCR3 + HO)/MSCs exhibited significantly decreased expression levels of downstream molecules, including phosphorylated (p)‑p38, p‑activated transcription factor 2, p‑C/EBP homologous protein‑10, and p‑myocyte enhancer factor 2C, and target molecules (e.g., apoptotic bodies). The effects of Ad‑(CXCR3 + HO)/MSCs on the repair of the damaged intestinal tract and inhibition of the p38‑MAPK pathway was more marked than those in other groups on day 7 post‑surgery in the rejection model for small bowel transplantation. BMMSCs modified by the CXCR3 and HO‑1 genes exhibited superior ability to repair damaged intestinal epithelial cells and served this role via the p38‑MAPK pathway.
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http://dx.doi.org/10.3892/ijmm.2019.4120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445595PMC
May 2019

Low free triiodothyronine is associated with contrast-induced acute kidney injury and long-term outcome in elderly patients who underwent percutaneous coronary intervention.

Anatol J Cardiol 2019 Feb;21(2):60-67

Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fujian Medical University; Fuzhou-China.

Objective: Low free triiodothyronine (fT3) is common in elderly patients with cardiovascular disease. The purpose of this study was to evaluate the relationship between low fT3 and contrast-induced acute kidney injury (CI-AKI), including the long-term outcomes, in elderly patients after a percutaneous coronary intervention (PCI).

Methods: A total of 350 patients aged ≥75 years who underwent PCI between January 2012 and December 2015 were consecutively enrolled. The perioperative thyroid function, including fT3, was measured before PCI. A low fT3 was defined as fT3<3.1 pmol/L with normal thyrotropin and free thyroxine. CI-AKI was defined as an absolute serum creatinine (SCr) increase ≥0.30 mg/dL or a relative increase in SCr ≥50% from the baseline value within 48 hours after contrast media exposure. A multivariate logistic regression analysis was applied to analyze whether low fT3 was an independent risk factor for CI-AKI. The Cox regression analysis was used to evaluate the relationship between low fT3 and long-term prognosis.

Results: A total of 46 (13.1%) patients developed CI-AKI. The incidence of CI-AKI was significantly higher in the low fT3 group than in the normal group (26.5% vs. 9.9%, p<0.01). A multivariable logistic analysis demonstrated that a low fT3 level was significantly related to CI-AKI [odds ratio (OR)=2.41; 95% confidence interval (CI), 1.11-5.27; p=0.027]. The Cox regression analysis showed that a low fT3 was associated with long-term mortality [adjusted hazard ratio (HR)=2.00; 95% CI, 1.04-3.83; p=0.037] during the follow-up of mean 1.67 years.

Conclusion: A low fT3 concentration was independently associated with CI-AKI and poor prognosis in elderly patients who had undergone PCI.
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http://dx.doi.org/10.14744/AnatolJCardiol.2018.38228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457427PMC
February 2019

Cyclic Peptide-Based Sirtuin Substrates.

Molecules 2019 Jan 24;24(3). Epub 2019 Jan 24.

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.

In the current study, four side chain-to-side chain cyclic peptides (three 5-mers and one 4-mer) harboring N-acetyl-lysine or N-myristoyl-lysine were found to be in vitro substrates of the human SIRT1/2/3-catalyzed deacylation with good substrate activities, as judged by the / ratios.
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http://dx.doi.org/10.3390/molecules24030424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384901PMC
January 2019

Cyclic tripeptide-based potent human SIRT7 inhibitors.

Bioorg Med Chem Lett 2019 02 12;29(3):461-465. Epub 2018 Dec 12.

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address:

In the current study, two cyclic tripeptides respectively harboring a thiourea-type and a carboxamide-type of catalytic mechanism-based sirtuin inhibitory warheads as the central residue were found to behave as potent (low μM level) inhibitors against the tRNA-activated human SIRT7 deacetylase activity. Despite exhibiting a potent pan-inhibition against the deacylase activities of the five tested human sirtuins (i.e. SIRT1/2/3/6/7), these two compounds represent the first examples of potent SIRT7 inhibitors ever identified thus far, and their identification could facilitate the future development of more potent and selective SIRT7 inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2018.12.023DOI Listing
February 2019

Prognostic evaluation of NANOG and OCT4 expression for posttransplantation hepatocellular carcinoma recurrence.

J Cell Biochem 2018 Dec 2. Epub 2018 Dec 2.

Tianjin Key Laboratory of Organ Transplantation, Tianjin, China.

Postoperative hepatocellular carcinoma (HCC) recurrence and metastasis throw great threaten to its overall survival (OS). This paper focus on exploring the prognostic significance of NANOG and OCT4 expression in HCC recurrence and OS after liver transplantation. Eighty-six patients who meet University of California San Francisco (UCSF) criteria and underwent liver transplantation in Tianjin First Central Hospital between August 2010 and August 2013 were included. Expression of NANOG and OCT4 was determined by immunohistochemistry. The relationships between NANOG and OCT4 expression with tumor recurrence, tumor count, histology stage, lymph node metastasis (LNM) and microvascular invasion (MVI) were explored through the χ test and Cox regression analysis. We found that 19/26 and 20/24 patients with positive expression of NANOG and OCT4 relapsed. Combination of NANOG and OCT4 expression was indicated as valuable prognostic signature for HCC recurrence prediction (P < 0.0011). Besides, we identified other key factors with significant correlations with recurrence, such as LNM (P = 0.011) and MVI (P = 0.024). Strikingly, recurrence sites could significantly affect recurrence time (P = 0.0062) and patients with recurrence in transplanted liver have longer recurrence time. In conclusions, we analyzed the relationships between NANOG/OCT4 expression, clinicopathology features, HCC recurrence, and OS after liver transplantation for the first time. Combination of NANOG, OCT4, LNM, histopathological stage, and MVI may be predictor for HCC recurrence posttransplantation. Comprehensive of histopathological stage grade and LNM were considered as prognosis factor for OS after liver transplantation. This should be helpful for treatment method selection for HCC patients after liver transplantation.
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http://dx.doi.org/10.1002/jcb.28128DOI Listing
December 2018

Encapsulation of verapamil and doxorubicin by MPEG-PLA to reverse drug resistance in ovarian cancer.

Biomed Pharmacother 2018 Dec 20;108:565-573. Epub 2018 Sep 20.

Department of Obstetrics and Gynecology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, China. Electronic address:

Purpose: Ovarian cancer is usually treated with transurethral resection or systemic chemotherapy in clinic. However, the development of drug resistance in ovarian cancer is frequently observed in ovarian cancer patients, leading to failure of tumor inhibition and recurrence. In this study, we aimed to efficiently reverse the drug resistance and enhance the anticancer effects by co-delivery of chemotherapeutic agents and multi-drugs resistant proteins inhibitor in ovarian cancer treatment.

Methods: The cell viability was measured by using MTT or flow cytometry (Annexin V/PI staining) under different culture conditions. Western blot was used to detect the expression of P-gp. We employed confocol to visualize the drug distribution under different culture systems. Using flow cytometry, we examined the drug absorption. MPEG-PLA was used to load chemotherapeutic drugs. We also applied mice model to evaluate the killing ability and side effects of free or methoxy poly (ethylene glycol)-poly (l-lactic acid) (MPEG-PLA) loaded drugs.

Results: We found that pre-treatment of verapamil, a multi-drugs resistant proteins inhibitor, could efficiently reverse the drug resistant in ovarian cancer. To further improve the pharmacokinetics profiles and avoid the systemic toxicity caused by agents, we encapsulated verapamil and doxorubicin (DOX) by polymeric nanoparticles MPEG-PLA. Co-delivery of verapamil and DOX by nano-carrier revealed reduced drug resistance and enhanced anticancer effects compared with the free drug delivery. More importantly, accumulated drugs, prolonged drug circulation and reduced systemic were observed in nanoparticles encapsulation group.

Conclusion: Co-delivery of verapamil and chemotherapeutic drugs by MPEG-PLA efficiently reversed the drug resistance, resulting in enhanced anticancer effects along with reduced systemic toxicity, which provides potential clinical applications for drug resistant ovarian cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2018.09.039DOI Listing
December 2018

CyclinD1 promotes lymph node metastasis by inducing lymphangiogenesis in human ovarian carcinoma.

Int J Clin Exp Pathol 2018 1;11(7):3726-3731. Epub 2018 Jul 1.

Department of Pathology, Shaoxing People's Hospital & Shaoxing Hospital, Zhejiang University Shool of Medicine Shaoxing, China.

Aims And Background: CyclinD1 regulates the G1/S phase transition of the cell cycle and is frequently overexpressed in many types of human cancers. Much evidence has implicated that the expression of CyclinD1 is related to the lymphatic metastasis of human ovarian carcinoma. However, the mechanism of CyclinD1 in lymphatic metastasis of ovarian carcinomas is still unclear. The objective of the present study was to assess the incidence of CyclinD1 expression in ovarian carcinomas and look for its correlation with lymph vessel density (LVD) and clinicopathological variables.

Methods: We assessed the expression of CyclinD1 levels and lymph vessel density (LVD) quantified through D2-40 by immunohistochemistry from 110 Chinese patients with primary ovarian carcinomas and 40 with benign ovarian tumors as controls.

Results: CyclinD1 was detected in 52 primary ovarian carcinomas (47.3%), which was significantly higher than its expression in the benign ovarian tumors. CyclinD1 expression was correlated with tumor grade, FIGO stage, T stage and lymphatic metastasis. Moreover, the LVD counts in the group of CyclinD1 positive expression were higher than in the group of CyclinD1 negative expression.

Conclusions: Our findings indicate that CyclinD1 might be involved in lymph node metastasis by inducing lymphangiogenesis in human ovarian carcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962868PMC
July 2018

Preface.

Authors:
Weiping Zheng

Prog Mol Biol Transl Sci 2018 ;154:ix-x

School of Pharmacy, Jiangsu University Zhenjiang, China.

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http://dx.doi.org/10.1016/S1877-1173(18)30029-2DOI Listing
January 2019

Mammalian Sirtuins SIRT4 and SIRT7.

Prog Mol Biol Transl Sci 2018 19;154:147-168. Epub 2018 Jan 19.

Jiangsu University, Zhenjiang, People's Republic of China. Electronic address:

Sirtuins are a family of intracellular enzymes whose enzymatic activities include catalyzing the β-nicotinamide adenine dinucleotide (β-NAD)-dependent N-acyl-lysine deacylation and the β-NAD-dependent mono-ADP-ribosylation. Among the seven sirtuin family members (i.e., SIRT1-7) thus far identified in mammals including humans, we know SIRT1/2/3/5/6 better than SIRT4/7 as for their enzymatic activities and the cellular roles of the reactions they catalyze. This chapter will provide an updated account on the enzymology and biology of SIRT4 and SIRT7, the two less well-understood mammalian sirtuins. It is hoped that this article will also be able to set a stage for the medicinal chemistry work on SIRT4 and SIRT7, potentially developing novel therapeutic agents for human diseases.
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http://dx.doi.org/10.1016/bs.pmbts.2017.11.001DOI Listing
January 2019

Chemical Probes in Sirtuin Research.

Prog Mol Biol Transl Sci 2018 27;154:1-24. Epub 2017 Dec 27.

Jiangsu University, Zhenjiang, People's Republic of China. Electronic address:

Sirtuins refer to a family of intracellular enzymes that are the yeast silent information regulator 2 (sir2) protein homologs found in organisms from all the three kingdoms of life. This family of enzymes primarily catalyze the protein N-acyl-lysine deacylation reaction despite the report for a type of bacterial/fungal sirtuins to robustly catalyze a protein mono-ADP-ribosylation reaction, however, these two group transfer reactions employ the redox coenzyme β-nicotinamide adenine dinucleotide (β-NAD) as the obligatory cosubstrate. Since 2000, in addition to histone proteins, more and more nonhistone proteins have also been identified as native substrates for the sirtuin-catalyzed deacylation, consistent with the ever-increased demonstration that this enzymatic reaction plays an important regulatory role in a variety of cellular processes, such as gene transcription and metabolism. This latter role is also consistent with the absolute dependence on β-NAD of the deacylation reaction catalyzed by sirtuin family members. The sirtuin-catalyzed deacylation has further been proposed as a contemporary therapeutic target for human diseases, such as cancer, neurodegenerative and metabolic diseases. In order to fully tap the therapeutic potential of the sirtuin-catalyzed deacylation, the past few years have witnessed a tremendous advancement in mechanistic elucidation, chemical modulator (inhibitor and activator) development, (chemical) biological and pharmacological exploration of the sirtuin-catalyzed deacylation reaction. During the journey of this knowledge advancement, the use of carefully designed chemical probes has played an elegant role. This chapter will delineate the development and application of these chemical probes in sirtuin research.
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http://dx.doi.org/10.1016/bs.pmbts.2017.11.014DOI Listing
January 2019

Effect of paiteling on human papillomavirus infection of the cervix.

Mol Clin Oncol 2017 Dec 17;7(6):957-964. Epub 2017 Oct 17.

Department of Obstetrics and Gynecology, Shanghai Pudong New Area People's Hospital, Shanghai 201299, P.R. China.

The aim of the present study was to investigate the effect of the traditional Chinese medicine paiteling on the outcome of high-risk human papillomavirus (HR-HPV) infection of the cervix. A total of 321 patients were enrolled in this study and HPV subtypes were determined by the Hybribio HPV genotyping system. The patients were divided into the loop electrosurgical excision procedure (LEEP; n=82) and non-LEEP (n=239) groups, according to the cervical intraepithelial neoplasia classification. These two groups were further subdivided into the drug (paiteling) and control subgroups. Thin-prep cytology and HR-HPV tests were performed every 3 months for 1 year. In the non-LEEP group, the negative conversion rate of HR-HPV and the regression rate of the cervical lesions in drug subgroup were significantly higher compared with those in the control subgroup. In the LEEP group, the seroconversion rate of the drug subgroup, but not the regression rate of the lesions, was significantly higher compared with that in the control subgroup. The seroconversion rate of HPV16-infected patients at 12 months was 85.7%, whereas it reached 100% in all other HPV subtypes. Therefore, paiteling may accelerate the clearance of HPV infection and the regression of cervical lesions.
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http://dx.doi.org/10.3892/mco.2017.1454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740912PMC
December 2017

Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction.

Bioorg Med Chem Lett 2017 12 12;27(24):5446-5449. Epub 2017 Nov 12.

School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address:

To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.
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http://dx.doi.org/10.1016/j.bmcl.2017.10.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711480PMC
December 2017

Protective effects of heme oxygenase-1-transduced bone marrow-derived mesenchymal stem cells on reduced‑size liver transplantation: Role of autophagy regulated by the ERK/mTOR signaling pathway.

Int J Mol Med 2017 Nov 6;40(5):1537-1548. Epub 2017 Sep 6.

Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, P.R. China.

Autophagy is a critical lysosomal pathway that degrades cytoplasmic components to maintain cell homeostasis and provide substrates for energy metabolism. A study revealed that heme oxygenase-1 (HO-1)-transduced bone marrow-derived mesenchymal stem cells (BM-MSCs) could protect 50% reduced-size liver transplantation (RSLT) in a rat model. However, the mechanisms remain mostly unknown. The aim of the present study was to explore the effects and related mechanism of autophagy on the protection conferred by HO-1-transduced BM-MSCs (HO-1/BM-MSCs) on 50% RSLT in a rat model. The authors established an acute rejection model following 50% RSLT in rats, with recipients divided into three groups receiving treatment with BM-MSCs, HO-1/BM-MSCs or normal saline (NS) injected through the dorsal penile vein. Transplanted liver tissues at 0, 1, 3, 5, 7, 10 and 14 days following transplantation were acquired for further analysis. The results indicated that the expression of autophagy-related proteins LC3 and Beclin-1 increased, the levels of ERK and p-ERK increased, and the levels of mammalian target of rapamycin (mTOR) and p-mTOR decreased in the HO-1/BM-MSCs. These observations indicated that autophagy is involved in the protective effects of HO-1/BM-MSCs on liver grafts following RSLT, possibly via upregulation of autophagy-related proteins through the ERK/mTOR signaling pathway.
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http://dx.doi.org/10.3892/ijmm.2017.3121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627878PMC
November 2017